BRPI0611773A2 - imidazo- and triazolopyridines, composition comprising them and use thereof - Google Patents

Abstract

IMIDAZO- AND TRIAZOLOPYRIDES, COMPOSITION UNDERSTANDING THE SAME AND USE OF THE SAME. The present invention relates to novel compounds which are provided which are type 1 11-beta-hydroxysteroid dehydrogenase inhibitors. Type 1 11-beta-hydroxysteroid dehydrogenase inhibitors are useful in treating, preventing, or reducing disease progression requiring type 1 11-beta-hydroxysteroid dehydrogenase inhibitory therapy. These novel compounds have the structure (1): either stereoisomers or pharmaceutically acceptable salts thereof, wherein W, L, R3, R3a, R ~ 3b ~ and R ~ 4 ~ are defined here.

Description

Report of the Invention Patent for "IMIDAZO-ETRIAZOLOPYRIDINES, COMPOSITION UNDERSTANDING THE SAME AND USE OF THE SAME".

BACKGROUND OF THE INVENTION

The present invention relates to cortisol steroid hormone which is a fundamental regulator of many physiological processes. However, an excess of cortisol, as occurs in Cushing's disease, causes severe metabolic abnormalities including: type 2 diabetes, cardiovascular disease, obesity, and osteoporosis. Many patients with these diseases, however, do not show significant increases in plasma cortisol levels. In addition to plasma cortisol, individual tissues can regulate their glucocorticoid tone by in situ conversion of inactive cortisol to the active hormone cortisol. In fact, the unusually high plasma cortisone concentration provides a ready-made precursor supply for conversion to cortisol via the 11-beta-hydroxysteroid dehydrogenase type I intracellular enzyme (11beta-HSD1).

Hbeta-HSDI is a member of the short chain dehydrogenase superfamily of enzymes. By catalyzing the conversion of cortisone to cortisis, 11beta-HSD1 controls intracellular glucocorticoid tone according to its expression and activity levels. In this way, 11beta-HSD1 can determine the overall metabolic state of the organ. 11beta-HSD1 is expressed at high levels in the liver and at lower levels in many metabolically active tissues including adipose, CNS, pancreas, and pituitary. Taking the liver as an example, it is predicted that high levels of 11beta-HSD 1 activity will stimulate gluconeogenesis and overall glucose production. Conversely, reduced activity of 11beta-HSD1 will sub-regulate glycogenesis resulting in lower plasma glucose levels.

Several studies have been conducted that support this hypothesis. For example, transgenic mice expressing 2X the normal level of 11beta-HSD1 in adipose tissue only have abdominal obesity, hyperglycemia, and insulin resistance. (H. Masuzaki, J. Paterson, H. Shin-yama, NM Morton, JJ Mullins, JR Seckl, JS Flier, A Transgenic Model of Vital Obesity and the Metabolic Syndrome, Science 294: 2166-2170 (2001). the 11beta-HSD1 gene is removed by homologous recombination, the resulting mice are resistant to diet-induced o-obesity and the resulting glucose metabolism dysregulation (NM Morton, JM Paterson, H. Masuzaki, MC Holmes, B. Sta- els, C. Fievet, BR Walker, JS Flier, JJ Mullings, JR Seckl, Novel Get Tissue-Mediated Resistance to Diet-induced Visceral Obesity in 11 β-Hydroxysteroid Dehydrogenase Type I-Deficient Mice Diabetes 53: 931-938 (2004)) In addition, the treatment of models of genetic obesity and diabetes mice (ob / ob, db / db and KKAy mice) with a specific inhibitor of 11 beta-HSD1 causes a decrease in glycoprotein production. of the liver and an overall increase in insulin sensitivity (P. Alberts, C.Nilsso n, G. Selen, L.O.M. Engblom, N.H.M. Edling, S. Norling, G. Klingstrom. Larsson, M. Forsgren, M. Ashkzari, C.E. Nilsson, M. Fiedler, E. Bergqvist, B. Ohman, E. Bjorkstrand, L.B. Abrahmsen, Selective Inhibition of 11β-Hydroxysteroid Dehydrogenase Type I Improves Hepatic Insulin Sensitivity in Hyperperglycemic Mice Strains, Endocrinoiogy 144: 4755-4762 (2003)). In addition, 11beta-HSD1 inhibitors have been shown to be effective in treating metabolic disorder and atherosclerosis in high fat fed mice (Hermanowoki-Vosetka et al., J. Eg. Med., 2002, 202 (4), 517-527). Based in part on these studies, it is believed that local control of cortisol levels is important in metabolic diseases in these model systems. In addition, the results of these studies also suggest that 11beta-HSD1 inhibition would be a viable strategy for treating metabolic diseases such as type 2 diabetes, obesity, and meta-colic syndrome.

Also supporting this idea are the results of a number of preliminary clinical studies. For example, several reports have shown that adipose tissue in obese individuals has high levels of 11beta-HSD1 reactivity. Furthermore, studies with carbenoxolone, a natural licorice-derived product that inhibits both 11beta-HSD1 and 11 beta-HSD2 (converting cortisol to cortisone in the kidney) showed promising results. A seven-day, double-blind, placebo-controlled, cross-sectional study with carbenoxolone in subjects with mildly overweight type 2 diabetes showed that patients treated with the inhibitor but not the placebo group showed a decrease in glycemic production. liver disease (RC Andrews, O. Rooyackers, BR Walker, J. Clin. Endocrinol. Metab. 88: 285-291 (2003)). This observation is consistent with inhibition of 11beta-HSD1 in the liver. The results of these early preclinical studies strongly support the concept that treatment with a potent and selective 11beta-HSD1 inhibitor is an effective therapy in patients suffering from type 2 diabetes, obesity, and metabolic syndrome.

SUMMARY OF THE INVENTION

In accordance with the present invention, aryl and heteroaryl and related compounds are provided which have the general structure of formula (I).

<formula> formula see original document page 4 </formula>

wherein W, L, R3, R3a, R3b and R4 are defined below.

The compounds of the present invention inhibit the activity of the 11-beta-hydroxysteroid dehydrogenase type I enzyme. Accordingly, the compounds of the present invention may be employed in the treatment of multiple diseases or disorders associated with 11-beta-hydroxysteroid dehydrogenase type I, such as such as diabetes and related conditions, microvascular complications associated with diabetes, macrovascular complications associated with diabetes, cardiovascular disease, metabolic syndrome and its component conditions, inflammatory diseases and other diseases. Examples of diseases or disorders associated with 11-beta-hydroxysteroid dehydrogenase type I enzyme activity that can be prevented, inhibited, or treated in accordance with the present invention include, but are not limited to, diabetes, hyperglycemia, impaired glucose tolerance. -injection, insulin resistance, hyperinsulinemia, retinopathy, neuropathy, neuropathy, delayed wound healing, atherosclerosis and its sequelae (acute coronary syndrome, myocardial infarction, angina pectoris, peripheral vascular disease, intermittent claudication), abnormal heart function, is -myocardialemia, stroke, Metabolic Syndrome, hypertension, obesity, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, high LDL, noncardiac ischemia, infection, cancer, vascular restenosis, pancreatitis, neurodegenerative disease, disorders delipids, cognitive impairment and dementia, bone disease, associated with HIV protease, glaucoma, and inflammatory diseases such as rheumatoid arthritis and osteoarthritis.

11beta-HSD1 inhibitors are also described in United States Patent Application Serial No. 11/448946, entitled "Bicycle 11-Beta Hydroxysteroid Dehydrogenase Type I Inhibitors", having the same cesarean section as the present invention and filed concurrently with it.

The present invention provides compounds of formula I, pharmaceutical compositions employing such compounds, and methods of employing such compounds. In particular, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, alone or in combination with a pharmaceutically acceptable carrier.

Further, according to the present invention, a method is provided for preventing, inhibiting, or treating the progression or onset of disease or disorders associated with the activity of the 11-beta-hydroxyesteroid dehydrogenase enzyme I as defined above and hereinafter, wherein a therapeutically effective amount of a compound of formula I is administered to a mammalian, i.e. human, patient in need of treatment.

The compounds of the invention may be employed alone, in combination with other compounds of the present invention, or in combination with one or more other agents. In addition, the present invention provides a method for preventing, inhibiting, or treating disease. as hereinbefore defined, wherein a therapeutically effective amount of a combination of a compound of formula I and another compound of formula I and / or at least one other type of therapeutic agent is administered to a mammalian patient, i.e. is human being in need of treatment.

DESCRIPTION OF THE INVENTION

In accordance with the present invention, compounds of formula I are provided

<formula> formula see original document page 6 </formula>

enantiomers, diastereomers, solvates, salts or prodrugs thereof:

W is aryl, cycloalkyl, heteroaryl or heterocyclyl, all of which may be optionally substituted with R1, R1a, R-1b, R1c β R4;

R1, R1a, R-1b, R1c and R1d are independently hydrogen, halogen, -OH, -CN, -NO2, -CO2R2a, -CONR2R2a, -SO2NR2R2a, -SOR2a, -SO2R2a, -NR2SO2R6, -NR2CO2R6, alkyl , haloalkyl, cycloalkyl, alkoxy, aryloxy, alkenyl, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamine, aminoalkyl, arylamine, heteroarylamine, aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, Rb, β R7c;

or alternatively any two R 1, R 1, R 1, R 1, R 1 and R 4 may be taken together to form a fused aryl, heteroaryl, heterocyclyl ring or heterocyclyl spiro ring;

L is a bond, O, S, SO, SO2, alkenyl, cycloalkyl, NR5, CR2R2a, CR2R2aCR2bR2Cι SO2NR2, OCR2R2a, OCR2R2aCR2a2, CR2bR2cCR2R2a2, CR2R2 CR2 CR2R2aSO2, SOCR2a2a, SO2CR2a2a, C R2 R2aOC R2b R2c, CR2R2aSCR2bRac CR2R2aSO2CR2bRac SO2NR2a2aR2b, CR2R2aCO1 CON25a2a2 CR2R2a2

R2, R2a, R2b and R2c are independently hydrogen, halogen, alkyl or haloalkyl;

or alternatively any two R 2, R 2a, R 2b, and R 2c may be taken together at the atom to which they are attached to form a halogen-substituted cycloalkyl, halo-substituted or heterocyclyl ring;

R3, R3a and R3b are independently hydrogen, halogen, -OH1 -CN, -NO2, -CO2R2a, -CONR2R2a, -SO2NR2R2a, -SOR2a, -SO2R2a, -NR2SO2R6, -NR2CO2R6, alkyl, haloalkyl, cycloalkyl, cycloalkyl, alkenyl, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamine, aminoalkyl, arylamine, heteroarylamine, aryl, heteroaryl or heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7;

R4 is bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl, both of which may optionally be substituted with one or more selected halogen substituents, -OH, -OR 6, -SR 6, -OCOR 6 -CN, -NR5COR6, -NR5SO2R6, -COR6, -CO2R6, -CO2H, -OCONR2R2a, -CONR2R2a, -NR5CO2R6, -SO2R6, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkoxy, aryl, heteroaryl or heterocyclyl may optionally be substituted with R 7, R 7a, R 7b, and R 7c; or

R4 is cycloalkyl, other than bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl, which may be optionally substituted by one or more substituents selected from halogen, -OH 1 -OR 6, -SR 6, - OCOR6, -CN, -NR5COR6, -NR5SO2R6, -COR6, -CO2R6, -CO2H, -OCONR2R2a, -CONR2R2a, -NR5CO2R6, -SO2R6, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, where a is alkyl aryl, heteroaryl or heterocyclyl may be optionally substituted by R 7, R 7a, R 7b, and R 7c; or

R4 is heterocyclyl, which may optionally be substituted by common or more substituents selected from halogen, -OH, -OR6, -SR6, -OCOR6, -CN1 -NR5COR6, -NR5SO2R6, -COR6, -CO2H, -COONR2R2a, - CONR 2 R 2a, -NR 5 CO 2 R 6, -SO 2 R 6, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted by R 7, R 7a, R 7b, and R 7c;

R 5 at each occurrence is independently hydrogen, alkyl, cycloalkyl, aryl, haloalkyl, COR 2a, CO 2 R 2a, SO 2 NR 2 R 2a, or SO 2 R 2a;

R 6 at each occurrence is independently alkyl, cycloalkyl, aryl or heteroaryl, all of which may be optionally substituted with R 7, R 7a, R 7b, and R 7c; and

R 7, R 7a, R 7b, and R 7c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amine, -OH, hydroxyalkyl heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamine, arylcarbonylamine, -NO 2, -CN or thiol.

In another embodiment, compounds of formula I are those wherein W is aryl, which is optionally substituted with R 1, R 1a, R 1b R 1c and R 1cj.

In another embodiment, compounds of formula I are those wherein W is phenyl, which is optionally substituted by R 1, R 1a, R 1b, R 1c and R 1d-.

In another embodiment, compounds of formula I are those wherein:

W is aryl, cycloalkyl or heteroaryl all of which may be optionally substituted with R1, R1a, R1b, R1c and R-icj;

R1, Ria, Rit>, Ric β R1ci are independently hydrogen, halogen, -OH, -CN1 -NO2, -CO2R2a, -CONR2R2a, -SO2NR2R2a, -SOR2a, -SO2R2a, -NR2SO2R6, -NR2CO2R6, alkyl, haloalkyl , cycloalkyl, alkoxy, aryloxy, alkenyl, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamine, aminoalkyl, arylamine, heteroarylamine, aryl, heteroaryl or heterocyclyl, wherein aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7b, and R7c;

L is a bond, O, S, SO, SO2, NR2, CR2R2a, CR2R2aCR2bR2c, SO2NR2, OCR2R2a CR2R2aO, SCR2R2a, CR2R2aS1 SOCR2R2a, SO2CR2R2a, CR2R2R2c2 Cr2R2c2

R2, R2a1 R2b and R2c are independently hydrogen, halogen, alkyl or haloalkyl;

R3, R3a and R3b are independently hydrogen, halogen, -OH, -CN, -NO2, -CO2R2a, -CONR2R2a, -SO2NR2R2a, -SOR2a, -SO2R2a, -NR2SO2R6, -NR2CO2R6, alkyl, haloalkyl, cycloalkyl, cycloalkyl, alkenyl, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamine, aminoalkyl, arylamine, heteroarylamine, aryl, heteroaryl or heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, Rzbi β R7c;

R4 is bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl both of which may be optionally substituted with one or more halogen-selected substituents, -OH, -OR 6, -SR 6, -OCOR 6, -CN, -NR 5 COR 6, -NR 5 SO 2 R 6 -COR 6, -CO 2 R 6, -CO 2 H, -OCONR 2 R 2a, -CONR 2 R 2a, -NR 5 CO 2 R 6, -SO 2 R 6, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, alkoxy, aryl, heteroaryl or heterocyclyl may optionally be substituted with R 7, R 7a, R 7b, and R 7c; or

R4 is cycloalkyl, other than bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl, which may be optionally substituted with one or more substituents selected from halogen, -OH, -OR6, -SR6, -OCOR6, -CN, -NR5COR6, -NR5SO2R6, -COR6, -CO2R6, -CO2H, -OCONR2R2a, -CONR2R2a, -NR5CO2R61 -SO2R6, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, where alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted by R 7, R 7a, R 7b, and R 7c; or

R4 is heterocyclyl which may optionally be substituted by one or more substituents selected from halogen, -OH, -OR6, -SR6, -OCOR6, -CN, -NR5COR6, -NR5SO2R6, -COR6, -CO2H, -OCONR2R2a, - CONR 2 R 2a, -NRsCO 2 R 6, -SO 2 R 6 Zaalkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted by R 7, R 7a, and R 7c; hydrogen, alkyl, cycloalkyl, aryl, haloalkyl, COFba or CO2Fba;

R 6 at each occurrence is independently alkyl, cycloalkyl, aryl or heteroaryl all of which may be optionally substituted with R 7, R 7a, R 7b, and R 7c; and

R 7, R 7a, R 7b, and R 7c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amine, -OH, hi-acyl , heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamine, arylcarbonylamine, -NO 2, -CN or thiol.

In another embodiment, compounds of formula I are those wherein:

W is aryl, cycloalkyl or heteroaryl all of which may be optionally substituted with R1, Ria, Rib, Ric and Ria;

R1, R1a, Rib, Ric and Rid are independently hydrogen, halogen, -OH, -CN1 -NO2, -CO2R2a, -CONR2R2a, -SO2NR2R2a, -SOR2a, -SO2R2a, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamine, aminoalkyl, arylamine, heteroarylamine, aryl, heteroaryl or heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7b, and R 7c;

L is a bond, O, S, SO1 SO2, NR2, CR2R2a, CR2R2aCR2bR2c, OCR2R2a, CR2R2aO, SCR2R2aS, CR2R2aS, CR2R2aSCR2bR2c, CR2R2b2c2R2R2c2;

R2, R2a, R2b and R2c are independently hydrogen, halogen, alkyl or haloalkyl;

R3, R3a and R3b are independently hydrogen, halogen, -OH, -CN, -NO2, -CO2R2a, -CONR2R2a, -SO2NR2R2a, -SOR2a, -SO2R2a, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkyl, arylsulfonyl, alkylamine, aminoalkyl, arylamine, heteroarylamine, aryl, heteroaryl or heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c; R4 is bicyclo [2,2,2] octyl or bicyclo [2,2,1 Jheptyl both of which may optionally be substituted with one or more selected halogen substituents, -OH, -OR 6, -SR 6, -OCOR 6, -CN, -COR 6, -CO 2 R 6, -CO 2 H , -OCONR 2 R 2a, -CONR 2 R 2a, -SO 2 R 6, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7ai R 7b, and R 7c ; or

R4 is cycloalkyl, other than bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl, which may be optionally substituted by one or more substituents selected from halogen, -OH, -OR 6, -SR 6, -OCOR6, -CN, -COR6, -CO2R6, -CO2H1 -OCONR2R2a, -CONR2R2a, -SO2R6, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may optionally substituted with R7, R7a, Ryb1 and R7c; or

R4 is heterocyclyl which may be optionally substituted by common or more substituents selected from halogen, -OH1-OR6, -SR6, -OCOR6, -CN, -COR61 -CO2R61 -CO2H, -OCONR2R2a, -CONR2R2ai -SO2R6, alkyl, alkoxy, aryl amine, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7b, and R 7c;

R 6 at each occurrence is independently alkyl, cycloalkyl, aryl or heteroaryl all of which may be optionally substituted with R 7, R 7a, R 7b, and R 7c; and

R 7, R 7a, R 7b, and R 7c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amine, -OH, hi-acyl , heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamine, arylcarbonylamine, -NO 2, -CN or thiol.

However in another embodiment, compounds of formula I are those wherein:

W is aryl or heteroaryl both of which may be optionally substituted with R1, R1a, R1b, Ric and Rid; R1, R1a, Rib. Ric and Rid are independently hydrogen, halogen, -OH 1-CN, -NO 2, -CO 2 R 2a, -CONR 2 R 2a, -SO 2 NR 2 R 2a, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkyl mine, aminoalkyl, arylamine, heteroarylamine, aryl, heteroaryl or heterocyclyl, wherein aryl, heteroaryl or heterocyclyl may optionally be substituted with R7, R7a, R7t>, and Fta;

L is a bond, O, S, SO, SO2, CR2R2a, OCR2R2a, CR2R2aO, SO2NR2CR2aR2b or CR2R2aOCR2bR2c;

R2, R2a, R2b and R2c are independently hydrogen, halogen, alkyl or haloalkyl;

R 3, R 3a and R 3b are independently hydrogen, halogen, -OH, -CN, -NO 2, -CO 2 R 2a, -CONR 2 R 2a, -SO 2 NR 2 R 2a, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylyl, alkylthio aminoalkyl, arylamine, heteroarylamine, aryl, heteroaryl or heterocyclyl, wherein aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7b, and R 7c;

R4 is bicyclo [2.2.2] octyl or bicyclo [2.2.1 Jheptyl both of which may be optionally substituted with one or more selected halogen substituents, -OH, -OR6, -SR6, -OCOR6, - CN, -COR 6, -CO 2 R 6, -CO 2 H, -OCONR 2 R 2a, -CONR 2 R 2a, -SO 2 R 6, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7b, and R 7c; or

R4 is cycloalkyl, other than bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl, which may be optionally substituted with one or more substituents selected from halogen, -OH, -OR6, -SR6, -OCOR6, -CN, -COR6, -CO2R6, -CO2H, -OCONR2R2a, -CONR2R2a, -SO2R6, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may optionally be substituted with R 7, R 7a, R 7b, and R 7c; or

R4 is heterocyclyl which may be optionally substituted by common or more substituents selected from halogen, -OH, -OR6, -SR6, -OCOR6, -CN, -COR6, -CO2R6, -CO2H, -OCONR2R2a, -CONR2R2a, -SO2R6, alkyl alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 'b, and R 7c;

R 6 at each occurrence is independently alkyl, cycloalkyl, aryl or heteroaryl all of which may be optionally substituted with R 7, R 7a, R 7b, and R 7c; and

R 7, R 7a, R 7b, and R 7c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amine, -OH, hi-acyl , heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamine, arylcarbonylamine, -NO 2, -CN or thiol.

In another embodiment, compounds of formula I are those wherein:

W is aryl or heteroaryl both of which may be optionally substituted with R1, R1a, Rib, R1c and R1d;

Ri, Ria, R-ibi Ric and Rid are independently hydrogen, halogen, -OH, -CN, -NO 2, -CO 2 R 2a, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamine, aminoalkyl, arylamine, heteroarylamine, aryl, heteroaryl or heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7b and R 7c;

L is a bond, O, S, SO, SO2, CR2R2a, OCR2R2a, CR2R2aO, SO2NR2CR2aR2b or CR2R2aOCR2bR2c;

R 2, R 2a> R 2b and R 2c are independently hydrogen, halogen, alkyl or haloalkyl;

R3. R 3a and R 3b are independently hydrogen, halogen, -OH, -CN, -NO 2, -CO 2 R 2a, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, ha-loalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamine, aminoalkyl, arylamine, heteroarylamine, , heteroaryl or heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may be optionally substituted by R 7, R 7a, R 7b, and R 7C.'R 4 is bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl both of which may optionally substituted with one or more selected halogen substituents, -OH, -OR6, -SR6, -CN1 -COR6, -CO2R6, -CO2H1 -CONR2R2a, -SO2R6, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted by R 7, R 7a, R 7t, and R 7c; or

R4 is cycloalkyl, other than bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl, which may be optionally substituted by one or more substituents selected from halogen, -OH, -OR61 -SR61 -CN -COR61 -CO 2 R 6, -CO 2 H 1 -CONR 2 R 2a, -SO 2 R 6, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7ai R 7t>, and Rzc; or

R4 is heterocyclyl which may be optionally substituted by common or more substituents selected from halogen, -OH, -OR6, -SR6, -CN, -COR6, -CO2R6, -CO2H, -CONR2R2ai -SO2R6, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, aryl, heteroaryl or heteroaryl may be optionally substituted with R 7, R 7a, R 7b, and R 7c;

R 6 at each occurrence is independently alkyl, cycloalkyl, aryl or heteroaryl all of which may be optionally substituted with R 7, R 7a, R 7b, and R 7c; and

R 7, R 7a, R 7b, and R 7c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amine, -OH, hi-acyl , heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamine, arylcarbonylamine, -NO 2, -CN or thiol.

However in yet another embodiment, compounds of formula are those wherein:

W is aryl which is optionally substituted with Ri, Ria, Rib, Rice Rid;

R 1, R 1a, Rib, R 1c and Rid are independently hydrogen, halogen, -OH, -CN, -NO 2, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamine, aminoalkyl, arylamine, heteroarylamine, aryl, heteroaryl or heterocyclyl, wherein aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7t>. and R7c;

L is a bond, O, S1 SO1 SO2, CR2R2a, OCR2R2a, CR2R2aO1SO2NR2CR2aR2b or CR2R2aOCR2bR2c;

R2, R2a, R2b and R2c are independently hydrogen, halogen, alkyl or haloalkyl;

R3, R3a and R3b are independently hydrogen, halogen, -OH1 -CN1 -NO2, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamine, heteroarylamine, aryl, heterocyclyl, wherein aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7b, and R 7c;

R 4 is bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl both of which may be optionally substituted with one or more selected halogen substituents, -OH, -OR 6, -SR 6, -CN, -COR6, -CO 2 R 6, -CO 2 H, -CONR 2 R 2a, -SO 2 R 6, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R7b, and R7c; or

R4 is cycloalkyl, other than bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl, which may be optionally substituted with one or more substituents selected from halogen, -OH, -OR6, -SR6, -CN, -COR 6, -CO 2 R 6, -CO 2 H, -CONR 2 R 2a, -SO 2 R 6, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R7a, R7b, and R7c;

R 6 at each occurrence is independently alkyl, cycloalkyl, aryl or heteroaryl all of which may be optionally substituted with R 7, R 7a, R 7b, and R 7c; and

R 7, R 7a, R 7b, and R 7c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amine, -OH, hydroxy , heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamine, arylcarbonylamine, -ΝΟ2, -CN or thiol.

In one embodiment, compounds of formula I are those wherein:

W is aryl which is optionally substituted with R1, R1a, R1b, R1c

and R1d;

R1, R1a, R1b, R1c and R1d are hydrogen, halogen, -OH1 -CN1 -NO2, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamine, aminoalkyl, aryl heteroaryl, heteroaryl wherein the aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7b and R 7c;

L is a bond, O, S, CR2R2a, OCR2R2a, CR2R2aO orC R2 R2aOC R2b R2CI

R2, R2a, R2b and R2c are independently hydrogen, halogen, alkyl or haloalkyl;

R3, R3a and R3b are independently hydrogen, halogen, -OH, -CN1 -NO2, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, aryl, heteroaryl or aryl heterocyclyl in which heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7b, and R 7c;

R4 is bicyclo [2.2.2] octyl or bicyclo [2.2.1 Jheptyl both of which may be optionally substituted with one or more selected halogen substituents, -OH, -OR6, -SR6, -CN, COR 6, -CO 2 R 6, -CO 2 H, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7b, and R 7c; or

R4 is cycloalkyl, other than bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl, which may be optionally substituted with one or more substituents selected from halogen, -OH, -OR6, -SR6, -CN, -COR 6, -CO 2 R 6, -CO 2 H, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7b, and R 7c ;

R 6, at each occurrence, is independently alkyl, cycloalkyl, aryl or heteroaryl; and

R7, R7a. R 7b, and R 7c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amine, -OH, hydroxyalkyl, heteroaryl, acyl heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamine, arylcarbonylamine, -NO 2, -CN or thiol.

However in yet another embodiment, compounds of formula are those wherein:

W is phenyl which is optionally substituted with R1, R1a, R1b, R1c and R1d;

R1, R1a, R1b, R1c and R1d are independently hydrogen, halogen, -OH, -CN1 -NO2, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamine, aminoalkyl, aryl heteroaryl or heterocyclyl;

L is O, S, SCH 2, OCH 2, CH 2 O or CH 2 OCH 2;

R3, R3a and R3b are independently hydrogen, halogen, -OH, -CN, -NO2, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, aryl, heteroaryl or heterocyclyl;

R 4 is bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl, all of which may be optionally substituted with one or more selected halogen substituents, -OH, -OR 6, -SR 6, -CN alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7b, and R 7c;

R 6 at each occurrence is independently alkyl, cycloalkyl, aryl or heteroaryl; and

R 7, R 7a> R 7b, and R 7c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylalkyl, cycloalkyl, amine, -OH, hydroxyalkyl, heteroaryl, heteroaryloxy, heteroarylalkyl, alkylthio, aryl, -NO2, or - CN.

However in yet another embodiment, compounds of formula are those wherein L is O.

However in yet another embodiment, compounds of formula are those wherein R 4 is bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl both of which may be optionally substituted with one or more halogen substituents selected from them. , -OH1-OR6, -SR6, -OCOR6, -CN1-NR5COR6, -NR5SO2R6, -COR6, -CO2R6, -CO2H1-OCONR2R2ai -CONR2R2a, -NR5CO2R6, -SO2R6, alkyl, alkoxy, aryl, heteroaryl, heterocyclyl, heterocyclyl wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may optionally be substituted with R 7, R 7a, R 7t, and R 7c.

In another embodiment, compounds of formula I are those compounds having formula IA:

<formula> formula see original document page 18 </formula>

on what:

L is selected from O, S, OCH2, CH2OCH2 and SO2NHCH2; and

R3, R3a and R3b are independently selected from hydrogen, halogen, CF3, OCF3, alkyl or alkoxy.

In another embodiment, compounds of formula I are those compounds having formula IA in which:

R1, R1a, R1b, R1c and R1d are independently hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, alkoxy, alkenyl, haloalkoxy, aryl, heteroaryl or heterocyclyl;

L is O;

R3, R3a and R3b are independently selected from hydrogen or halogen; and

R 4 is bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl both of which may be optionally substituted with one or more selected halogen substituents, OH, OR 6, OCOR 6, haloalkyl, haloalkoxy, aryl, heterocyclic; e R6 is alkyl or cycloalkyl.

In another embodiment, compounds of formula I are those compounds having formula IA in which:

L is selected from O, OCH2 and CH2OCH2;

R4 is bicyclo [2.2.2] octyl or bicyclo [2.2.1 Jheptyl both of which may be optionally substituted with one or more selected halogen substituents, -OH1 -OR6, -SR6, -OCOR61 -CN1 - NR5COR6, -NR5SO2R6, -COR61 -CO2R61 -CO2H1 -OCONR2R2ai -CONR2R2a, -NR5CO2R6l -SO2R61 alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein the optionally alkyl, alkoxy, aryl or heteroaryl may be alkyl, aryl R7, R7a, R7bl and R7c; or

R4 is cycloalkyl, other than bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl, which may be optionally substituted by one or more substituents selected from halogen, -OH 1 -OR 6, -SR 6, - OCOR6, -CN1 -NR5COR61 -NR5SO2R6, -COR6, -CO2R6, -CO2H, -OCONR2R2a, -CONR2R2a, -NR5CO2R6, -SO2R6, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, where alkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted by R 7, R 7a, R 7t, and R 7c; and

R 6 at each occurrence is independently alkyl or cycloalkyl.

In another embodiment, compounds of formula I are those compounds having formula IA in which:

L is selected from O1 OCH2 and CH2OCH2;

R4 is a fused or bridged cycloalkyl other than bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl, which may optionally be substituted with one or more substituents selected from halogen, - OH, -OR6, -SR6, -OCOR6, -CN, -NR5COR6, -NR5SO2R6, -COR6, -CO2R6, -CO2H, -OCONR2R2a, -CONR2R2a, -NR5CO2R6, -SO2R6, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7bl and R 7c; and

R 6 at each occurrence is independently alkyl or cycloalkyl. In another embodiment, compounds of the present invention are selected from the compounds exemplified in the examples, such as Examples 9, 11 and 100 to 113.

In another embodiment, the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of the present invention alone or optionally in combination with a pharmaceutically acceptable carrier and / or one or more other agent (s). (s).

In another embodiment, the present invention relates to methods for inhibiting 11-beta-hydroxysteroid dehydrogenase type I enzyme activity comprising administering to a mammalian patient, for example, a human patient, in need thereof a therapeutically effective amount of a compound of the present invention, alone, or optionally in combination with another compound of the present invention and / or at least one other type of therapeutic agent.

In another embodiment, the present invention relates to a method for preventing, inhibiting, or treating the progression or onset of diseases or disorders associated with the activity of the 11-beta-hydroxysteroid dehydrogenase type I enzyme comprising administering to a patient, for example a human patient, in need of prevention, inhibition, or treatment of a therapeutically effective amount of a compound of the present invention alone, or optionally in combination with another compound of the present invention and / or at least one other type of therapeutic agent.

Examples of diseases or disorders associated with 11-beta-hydroxysteroid dehydrogenase type I enzyme activity that may be prevented, inhibited, or treated in accordance with the present invention include, but are not limited to, diabetes, hyperglycemia, glucose tolerance. impaired insulin resistance, hyperinsulinemia, retinopathy, neuropathy, nephropathy, delayed wound healing, atherosclerosis, acute coronary syndrome, myocardial infarction, angina pectoris, peripheral vascular disease, intermittent claudication, abnormal heart function, myocardial ischemia, stroke, metabolic syndrome, hypertension, obesity, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, high LDL, non-cardiac ischemia, infection, cancer, restenosevascular, pancreatitis, neurodegenerative disease, lipids, cognitive impairment and dementia, bone disease, asodynia with HIV protease, glaucoma, rheumatoid arthritis and osteoarthritis.

In another embodiment, the present invention relates to a method for preventing, inhibiting, or treating the progression or onset of diabetes, hyperglycemia, obesity, dyslipidemia, hypertension, cognitive impairment, rheumatoid arthritis, osteoarthritis, glaucoma, and metabolic syndrome comprising administering to a mammalian patient, for example, a human patient in need of prevention, inhibition, or treatment of a therapeutically effective amount of a compound of the present invention, alone or, in combination, with another compound of the present invention. and / or at least one other type of therapeutic agent.

In yet another embodiment, the present invention relates to a method for preventing, inhibiting, or treating the progression or onset of diabetes, comprising administering to a mammalian patient, for example, a human patient in need of prevention, inhibition, or treatment. of a therapeutically effective amount of a compound of the present invention alone or, optionally, in combination with another compound of the present invention and / or at least one other type of therapeutic agent.

In yet another embodiment, the present invention relates to a method for preventing, inhibiting, or treating the progression or onset of hyperglycemia comprising administering to a mammalian patient, for example, a human patient in need of prevention, inhibition, or other treatment. a therapeutically effective amount of a compound of the present invention alone or optionally in combination with another compound of the present invention and / or at least one other type of therapeutic agent.

In another embodiment, the present invention relates to a method for preventing, inhibiting, or treating the progression or onset of obesity comprising administering to a mammalian patient, for example, a human patient, in need of prevention, inhibition. or treating a therapeutically effective amount of a compound of the present invention alone or, optionally, in combination with another compound of the present invention and / or at least one other type of therapeutic agent.

In one embodiment, the present invention relates to a method for preventing, inhibiting, or treating the progression or onset of dyslipidemia comprising administering to a mammalian patient, for example, a human patient, in need of prevention, inhibition. or treating a therapeutically effective amount of a compound of the present invention alone or, optionally, in combination with another compound of the present invention and / or at least one other type of therapeutic agent.

In another embodiment, the present invention relates to a method for preventing, inhibiting, or treating the progression or onset of hypertension comprising administering to a mammalian patient, for example, a human patient in need of prevention, inhibition, or inhibition. or treating a therapeutically effective amount of a compound of the present invention alone or, optionally, in combination with another compound of the present invention and / or at least one other type of therapeutic agent.

In another embodiment, the present invention relates to a method for preventing, inhibiting, or treating the progression or onset of cognitive impairment comprising administering to a mammalian patient, for example, a human patient, in need of preventing, inhibiting, or treating a therapeutically effective amount of a compound of the present invention alone or, optionally, in combination with another compound of the present invention and / or at least one other type of therapeutic agent.

In another embodiment, the present invention relates to a method for preventing, inhibiting, or treating the progression or onset of arthritis, comprising administering to a mammalian patient, for example, a human patient in need of prevention, inhibition, or inhibition. or treating a therapeutically effective amount of a compound of the present invention alone or, optionally, in combination with another compound of the present invention and / or at least one other type of therapeutic agent.

In another embodiment, the present invention relates to a method for preventing, inhibiting, or treating the progression or onset of osteoarthritis comprising administering to a mammalian patient, for example, a human patient, in need of prevention, inhibition or treating a therapeutically effective amount of a compound of the present invention alone or, optionally, in combination with another compound of the present invention and / or at least one other type of therapeutic agent.

In another embodiment, the present invention relates to a method for preventing, inhibiting, or treating the progression or onset of Metabolic Syndrome comprising administering to a mammalian patient, for example, a human patient in need of prevention, inhibition. , treating a therapeutically effective amount of a compound of the present invention alone or, optionally, in combination with another compound of the present invention and / or at least one other type of therapeutic agent.

In another embodiment, the present invention relates to a method for preventing, inhibiting, or treating the progression or onset of glaucoma comprising administering to a mammalian patient, for example, a human patient in need of prevention, inhibition, or treating a therapeutically effective amount of a compound of the present invention alone or, optionally, in combination with another compound of the present invention and / or at least one other type of therapeutic agent.

DEFINITIONS

The compounds described herein may have asymmetric centers.

Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optionally active or racemic forms. It is well known in the art to prepare optically active forms, such as by solving racemic forms or by synthesizing optionally active starting materials. Many geometric isomers of olefins, C = N double bonds, and the like may also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Useful geometric and transomers derived from the present invention are described and may be isolated as a mixture of isomers or as isolated isomeric forms. All chiral, diastereomeric, racemic, and all geometric isomeric forms of a structure are intended unless the specific stereochemistry or isomeric form is specifically indicated.

The term "substituted" as used means that any one or more hydrogens on the designated atom or ring is substituted with a selection from the indicated group, provided that the normal value of the designated atom is not exceeded and that the substitution results in a stable compound. . When a substituent is keto (ie = 0) then 2 hydrogens on the atom are substituted.

When any variable (for example, Ra) occurs more than once in any constituent or formula for a compound, its definition of each occurrence is independent of its definition for each other occurrence. Therefore, for example, if a group is shown to be replaced with The a2 Ra, then said group may optionally be substituted with up to two groups Ra and Ra at each occurrence is independently selected from the Ra definition. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

When a bond to a substituent indicates to bond a bond by connecting two atoms in a ring, then that substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom whereby such substituent is attached to the rest of the compound of a given formula, then such substituent may be attached by any atom in such substituent. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

Unless otherwise indicated, the terms "lower alkyl", "alkyl", or "alk" as used herein alone or as part of another group include both straight or branched chain hydrocarbons containing 1 to 20 carbons. preferably 1 to 10 carbons, more preferably 1 to 8 carbons, in the normal chain, such as methyl, ethyl, propyl, iso-propyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4, 4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various branched chain isomers thereof and the like as well as such groups may optionally include 1 to 4 substituents such as halo, for example F, Br, Cl, or CF3, alkyl, alkoxy, aryl, aryloxy, aryl (aryl) or diaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amine, hydroxy, hydroxyalkyl, acyl, heteroaryl heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, ar ylalkylthio, aryloxyalea, alkylamido, alkanoylamine, arylcarbonylamine, nitro, cyano, thiol, haloalkyl, trialoalkyl, and / or alkylthio alkylthio.

Unless otherwise indicated, the term "cycloalkyl" as used alone or as part of another group includes saturated or partially unsaturated cyclic hydrocarbon groups (containing 1 or 2 double bonds) containing 1 to 3 rings, including monocyclic alkyl, alkylade bicyclic (or bicycloalkyl) and tricyclic alkyl, containing a total of 3 to 20 carbons forming the ring, preferably 3 to 10 carbons, forming the ring which may be fused to 1 or 2 aromatic rings as described for parayl, which includes cyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl, cycloeptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl, any of which groups may be optionally substituted with 1 to 4 substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy, arylalkyl, cycloalkyl, alkylamido, alkanoylamine, oxo, acyl, arylcarbonylamine, amine, nitro, cyano, thiol, and / or alkylthio and / or any of the paraalkyl substituents. and otherwise indicated, the term "lower alkenyl" or "alkenyl" as used herein alone or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons, and more preferably 1 to 8 normal chain carbons which include one to six normal chain double bonds, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl , 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, esimilar, and which may optionally be substituted with 1 to 4 substituents, ie, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amine, hydroxy, heteroaryl, cycloheteroalkyl, alkanoylamine, alkylamido, arylcarbonyl amine, , cyano, thiol, alkylthio, and / or any of the alkyl substituents shown herein.

Unless otherwise indicated, the term "lower alkynyl" or "alkynyl" as used herein alone or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons, and more preferably 2 to 8 normal chain carbons, which include a triple bond in the normal chain, such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentinyl, 3-pentinyl, 2-hexinyl, 3- hexinyl, 2-heptinyl, 3-heptinyl, 4-heptinyl, 3-octinyl, 3-noninyl, 4-decinyl, 3-undecinyl, 4-dodecinyl, and the like, and which may be optionally substituted with 1 to 4 substituents i.e. halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amine, heteroaryl, cycloheoalkyl, hydroxy, alkanoylamine, alkylamido, arylcarbonylamine, nitro, cyano, thiol, alkylthio and / or any substituents presented herein.

Where alkyl groups as defined above have unique bonds for bonding to other groups on two different carbon atoms, they are called "alkylene" groups and may optionally be substituted as defined above for "alkyl."

Where alkenyl groups as defined above and dealinyl groups as defined above, respectively, have unique bonds to paralyze other groups at two different carbon atoms, they are referred to as "alkenylene groups" and "alkynylene groups", respectively, and may optionally be substituted as defined above for "alkenyl" and "alkynyl".

The term "halogen" or "halo" as used herein alone or as part of another group refers to chlorine, bromine, fluorine, and iodine as well as CF3, with chlorine or fluorine being preferred.

Unless otherwise indicated, the term "aryl" as used herein alone or as part of another group refers to aromatic monocyclic and bicyclic groups containing 6 to 10 carbons in the forward moiety (such as phenyl or naphthyl, including 1-naphthyl and 2-naphthyl) and may optionally include 1 to 3 additional rings fused to a carbocyclic ring or heterocyclic ring (such as aryl, cycloalkyl, heteroaryl, or cycloetheroalkyl rings

for example

<formula> formula see original document page 27 / formula>

and may optionally be substituted by suitable carbon atoms with 1, 2, or 3 substituents, for example hydrogen, halo, haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkylalkyl, cycloetheroalkyl , cycloetheroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, arylthio, arylazo, heteroarylalkyl, heteroarylarylaryl, heteroarylaryl, hydroxy, amine, substituted or amine, 2-amine, cyanoidine are alkyl, aryl, or any of the other aryl compounds mentioned in the definitions), thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkoxy-rithio, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonyl, alkylcarbonyl alkylcarbonylamine, arylcarbonylamine, arylsulphinyl, arylsulphinylalkyl, arylsulphonylamine, or arylsulphonyl aminocarbonyl, and / or any of the alkyl substituents herein.

Unless otherwise indicated, the term "lower alkoxy", "alkoxy", "aryloxy" or "aralkoxy" as used herein alone or as part of another group includes any of the above alkyl, aralkyl or aryl groups attached to an oxygen atom.

Unless otherwise indicated, the term "amine" as used herein alone or as part of another group refers to the amino which may be substituted with one or two substituents which may be the same or different, such as alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloetheroalkyl, cycloetheroalkylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or thioalkyl. These substituents may also be substituted with a carboxylic acid and / or any of the groups R1 or substituents for R1 as set forth above. In addition, amine substituents may be taken together with the denitrogen atom to which they are attached to form 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4- alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, 1-pyrrolidinyl, 1-piperidinyl, or 1-azepinyl, optionally substituted with coalkyl, alkoxy, alkylthio, halo, trifluoromethyl, or hydroxy.

Unless otherwise indicated, the term "lower alkylthio," "alkylthio," "arylthio," or "aralkylthio" as used herein alone or as part of another group includes any of the alkyl, aralkyl, or aryl above groups referred to in a sulfur atom.

Unless otherwise indicated, the term "lower alkylamino," "alkylamine," "arylamine," or "arylalkylamino" as used herein or as part of another group includes any of the above alkyl, aryl, or arylalkyl groups to a nitrogen atom.

As used herein, the term "heterocyclyl1" or "heterocyclic system" is intended to mean a stable 4- to 12-membered monocyclic or bicyclic heterocyclic ring that is saturated, or partially unsaturated, consisting of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, NH1 O, and S1 and including any bicyclic group in which any of the above defined heterocyclic rings is fused to a benzene ring.Nitrogen and sulfur heteroatoms may optionally be oxidized The heterocyclic ring may be attached to its pendant group on any heteroatom or carbon atom that results in a stable structure The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if resultant compound is stable If specifically mentioned, a nitrogen in the heterocycle may optionally be quaternized.

It is preferred that when the total number of atoms of S and O in heterocycle exceeds 1, then these heteroatoms are not adjacent to each other. As used herein alone or as part of the other group refers to a 5- or 12-membered aromatic ring. preferably a 5or 6-membered aromatic ring including 1, 2, 3, or 4 heteroatoms such as nitrogen, oxygen, or sulfur, and such rings fused to an aryl, cycloalkyl, heteroaryl, or cycloetheroalkyl ring (e.g. benzothiophenyl, indolyl), and includes possible N-oxides. The heteroaryl group may optionally include 1 to 4 substituents such as any of the substituents shown above for alkyl. Examples of heteroaryl groups include the following:

Unless otherwise indicated, the term "heteroaryl" such as <formula> formula see original document page 30 </formula>

and the like.

The term "heterocyclylalkyl" or "heterocyclyl" as used herein alone or as part of another group refers to heterocyclyl groups as defined above attached through a C atom or heteroatom to an alkyl chain .

The term "heteroarylalkyl" or "heteroarylalkenyl" as used herein alone or as part of another group refers to heteroaryl groups as defined above attached via a C or heteroatom atom to an alkyl chain alkylene or alkenylene as defined above.

The term "cyano" as used herein refers to a CN group.

The term "nitro" as used herein refers to a NO 2 group.

The term "hydroxy" as used herein refers to an OH group.

The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of safe medical diagnosis, suitable for use in contact with human and human tissues. animals without excessive toxicity, irritation, allergic response, or other commensurate problem or complication with a reasonable benefit / risk ratio.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the source compound is modified by preparing base or acid salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; organic or alkali salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the source compound formed, for example, of non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the prepared salts of organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamic, maleic, hydroximaletic, phenyl-skeptic, glutamic, benzoic, salicylic, sulfanil, 2 -acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

Pharmaceutically acceptable salts of the present invention may be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts may be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the base or suitable acid in water or an organic solvent, or a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. Suitable salt lists are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

Any compound that can be converted in vivo to provide the bioactive agent (i.e. the compound of formula I) is a prodrug within the scope and spirit of the invention.

The term "prodrugs" as used herein includes phosphate, esters and carbonates formed by reacting one or more hydroxyls of the compounds of formula I with alkyl, alkoxy, or aryl substituted phosphorylation or acylating agents employing procedures known to those skilled in the art. to generate phosphates, acetates, pivalates, methylcarbonates, benzoates, and the like.

Various forms of prodrugs are well known in the art and are described in: a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch. 31 (Academic Press, 1996);

b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985);

c) The Textbook of Drug Design and Deveriopment, P. Krogsgaard-Larsonand H. Bundgaard, eds. Ch. 5, pp. 113-191 (Harwood Academic Publishingers, 1991); and

d) Hydroysis in Drug and Prodrug Metabolism, Bernard Testa and Joa-chim M. Mayer, (Wiley-VCH, 2003).

Said references are incorporated herein by reference.

In addition, compounds of formula I are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 99% decomposed of formula I (substantially pure compound I "). ") which is then employed or formulated as described herein. Such "substantially pure" compounds of formula I are also contemplated herein as part of the present invention.

All stereoisomers of the compounds of the present invention are contemplated either in admixture or in pure or substantially pure form. The compounds of the present invention may have asymmetric centers of carbon atoms and include any of the substituents R and / or exitly well polymorphism. Accordingly, the compounds of formula I may exist in enantiomeric or diastereomeric forms or in mixtures thereof. Processes for preparation may use racemates, enantiomers, or diastereomers as starting materials. When diastereomeric or enantiomeric products are prepared, they may be separated by conventional methods, for example, fractional crystallization or chromatography.

"Stable combination" and "stable structure" are intended to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity of a reaction mixture, and formulation into an effective therapeutic agent. The present invention is intended to incorporate stable compounds. "Therapeutically effective amounts" is intended to include an amount of a compound of the present invention alone or a quantity of the combination of claimed compounds or a quantity of a compound of the present invention in combination with other effective active ingredients. to inhibit 11beta-HSD1 or effectively treat or prevent diseases or disorders associated with 11beta-HSD 1.

As used herein, "treating" or "treating" encompasses treating a disease state in a mammal, particularly in a human, and includes: (a) preventing the disease state from occurring in a mammal, in particular when such a mammal is predisposed to the finger state but has not yet been diagnosed as having it; (b) inhibit the disease state, i.e. stop its development; and / or (c) alleviate the disease state, that is, cause regression of the disease state.

SYNTHESIS

Compounds of formula I may be prepared as shown in the following reaction schemes and description thereof, as well as procedures in the relevant literature which may be employed by one of ordinary skill in the art. Exemplary reagents and procedures for these reactions appear hereinafter and in the Working Examples.

Scheme I

<formula> formula see original document page 33 </formula>

Scheme I describes a method for preparing compounds of formula IB (a subgroup of compounds of formula I). A phenol II intermediate can be obtained commercially, prepared by methods known in the literature or by other methods known to one skilled in the art. Formation of a Compound IB may be carried out from an amphenol II and an III alcohol employing triphenylphosphine and DEAD or DIAD, commonly known as the Mitsunobu Reaction. Alternatively, compound IB may be obtained by alkylation of a phenol II with an IV chloride or V bromide in the presence of an appropriate base such as cesium carbonate, potassium carbonate, sodium carbonate or DIEA.

Scheme Il

<formula> formula see original document page 34 </formula>

Scheme II describes a method for preparing compounds of formula IC and formula ID (subgroups of compounds of formula I). Thiophenol IV intermediate can be obtained commercially, prepared by methods known in the literature or by other methods known to one of skill in the art. Formation of a compound IC may be achieved by alkylation of a thiophenol V1 with an IV chloride or a V bromide in the presence of an appropriate base such as sodium carbonate or DIEA. Subsequent oxidation of a 1C compound with a suitable oxidation reagent such as / 77CPBA, Oxone®, generalized p-toluenesulfonic peracid in situ (Tetrahedron, 1996. 52, 5773-5787) or other known reagents. skilled in the art provides a compound 1 D. SCHEME III

<formula> formula see original document page 35 </formula>

Scheme III describes a method for preparing compounds of formula IE (a subgroup of compounds of formula I). An arylsulfonyl chloride intermediate VII may be obtained commercially, prepared by methods known in the literature or by other methods known to one skilled in the art. Formation of an IE compound can be obtained by reacting a compound of formula VII with an amine VIII in the presence of an appropriate base such as pyridine, DIEA or other reagents known to one skilled in the art to disperse a compound 1E.

SCHEME IV

<formula> formula see original document page 35 </formula>

Scheme IV describes a method for preparing compounds of formula IF (a subgroup of compounds of formula I). A phenol II intermediate may be obtained commercially, prepared by methods known in the literature or by other methods known to one of ordinary skill in the art. Formation of an IF compound can be obtained by treating a potassium salt of a phenol II and a bromine or iodine substituted intermediate IX (Z is Br or I) in the presence of high temperature copper powder or salt. , commonly known as the Ullmann Coupling Reaction (Tetrahedron, 1984, 40, 1433-1456). Alternatively, an IF compound may be obtained from an SNAr reaction of a phenol II and an intermediate substituted by bromine, chlorine or fluorine IX (Z is Br, Cl or F) in the presence of a base such as potassium hydride, sodium hydride, cesium carbonate, high temperature potassium carbonate. Both Ullmann Couplings and SNAr reactions can be performed under a conventional procedure or performed in a microwave reactor.

SCHEME V

<formula> formula see original document page 36 </formula>

Scheme V describes an alternative method for preparing compounds of formula IF (a subgroup of compounds of formula I). Phenol II or arylboronic acids X1 can be obtained commercially, prepared by methods known in the literature or by other methods known to one skilled in the art. Formation of an IF compound can be obtained from a promoted acetate-decrylated aryl ether synthesis employing a phenol II and arylboronic acid X or a phenol X11 and an arylboronic acid X1 (Tetrahedron Lett., 1998, 39, 2937-2940). Vl

<formula> formula see original document page 37 </formula>

Schemes I to V

Scheme V1 describes a method for preparing compounds of formula IA (a subgroup of compounds of formula I). A fluorine, chlorine or bromopyridine intermediate III can be obtained commercially prepared by methods known in the literature or by other methods known to one skilled in the art. An appropriate protecting group (PG) may be employed for intermediate X11 (for example, a TBS group or another as an alcohol protecting group) for better reaction compatibility. Reaction of a compound of formula X11 with hydrazine was carried out at an elevated temperature to provide an intermediate XIV. Acylation of an XIV intermediate with an XV acid employing an appropriate group of amide coupling reagents such as NMM / isobutylchoformate, EDAC / HOBT or other reagents described in "The Practice of Peptide Synthesis" (Spring-Verlag, 2nd Edition, Bodanszy, Miklos , 1993) provides a hydrazide intermediate XVII. Alternatively, a hydrazide XVII may be prepared by reacting a compound of formula XIV and an acid chloride XVI in the presence of an appropriate base such as DIEA or TEA. The formation of 1,2,4-triazolopyridine XVIII can be obtained from the reaction of XVII with POCI3 at an elevated temperature. The formation of 1,2,4-triazolopyridine XVIII can also be obtained from XVII in the presence of acetic acid at an elevated temperature, or under a conventional procedure or microwave reactor. Alternatively, formation of 1,2,4-triazolopyridine XVIII may be obtained by reacting XVII with Ph3PCI2 in the presence of a base such as TEA or by other methods known to one skilled in the art. The protecting group, if present, may be removed from a compound of formula XVIII to provide an intermediate XIX (for further examples of protecting group and conditions for removal thereof, see Protevtive Groups in Organic Synthesis Greene and others). , John Wiley and Sounds Inc., 1991). Alternatively, compounds wherein L-PG is a suitable group functional, such as Br, Cl, F, and the like, may also be converted to formula 1A by means of this Scheme VI. Formation of a compound of formula 1A may be accomplished by employing reactions described in Schemes I to V or by other methods known to one of ordinary skill in the art.

Scheme Vll

<formula> formula see original document page 38 </formula>

Scheme VII describes an alternative method for preparing compounds of formula IA (a subgroup of compounds of formula I). Fluorine, chlorine or bromopyridine XX can be obtained commercially, prepared by methods known in the literature or by other methods known to one skilled in the art. The Li group in XX is an appropriate functional group which may form intermediate XXI by the reactions described in Schemes I to V or by other methods known to one skilled in the art. Reaction of a compound of formula XXI with hydrazine was performed at an elevated temperature to provide an intermediate XXII. Acylation of an intermediate XXII with an XV acid by employing an appropriate group of amide coupling reagents such as NMM / isobutylchoformate, EDAC / HOBT or other reagents described in "The Practice of Peptide Synthesis" (Spring-Verlag, 2nd Edition, Bodanszy , Miklos, 1993) provide a hydrazide intermediate XXIII. Alternatively, a hydrazide XXIII may be prepared from the reaction of a compound of formula XXII and an acid chloride XVI in the presence of an appropriate base such as DIEA or TEA. The formation of 1,2,4-triazolopyridine IA can be obtained from the reaction of XXIII with POCI3 at an elevated temperature. The formation of 1,2,4-triazolopyridine IA may also be obtained from XXIII in the presence of acetic acid at an elevated temperature, or under a conventional procedure or microwave reactor. Alternatively, 1,2,4-triazolopyridine IA formation can be obtained by reacting XXIII with Ph3PCfe in the presence of a base such as TEA or by other methods known to one of skill in the art.

Scheme Vlll

<formula> formula see original document page 39 </formula>

Scheme VII describes a method for preparing compounds of formula IG (a subgroup of compounds of formula I). A 4-fluorine or 4-chloronitrobenzene intermediate can be obtained commercially, prepared by methods known in the literature or by methods known to one skilled in the art. A reaction of compounded SwAr XXIV with 2-fluoro- or 2-chloro-3-hydroxylpyridine compound XXV in the presence of a base such as cesium carbonate or potassium carbonate provides compound XXVI. Reduction of the nitro group in compound XXVI may be obtained under the condition of hydrogenation, iron powder in aqueous ethanol solution or other methods known in the literature to provide aniline intermediate XXVII. Removal of the amine group in compound XXVII can be obtained from treatment of compound XXVII with hydrochloric acid and sodium nitrite followed by hypophosphorus (N. Kornblum, Org.Syn. Ill 1955, 295-297). Alternatively, compound XXVIII can be obtained by reacting compound XXVII with butyl nitrite in DMF (M. Doyle, et al. J. Org. Chem. 1977, 42, 3494-3497). Reaction of 2-fluoro- or 2-chloropyridine Compound XXVII1 with hydrazine may be performed at an elevated temperature to provide an intermediate XXIX. Acylation of an intermediate XXIX with an XV acid employing an appropriate group of amide-coupling reagents such as NMM / isobutylchoformate, EDAC / HOBT or other reagents described in "The Practice of Peptide Synthesis" (Spring-Verlag, 29 Edition, Bodanszy, Miklos, 1993). ) provide a XXX hydrazide intermediate. Alternatively, a XXX hydrazide may be prepared to give a compound of formula XXIX and an acid chloride XVI in the presence of an appropriate base such as DIEA or TEA. The formation of 1,2,4-triazolopyridine IG can be obtained by reacting XXX with POCI3 at a high temperature. The formation of 1,2,4-triazolopyridine IG can also be obtained from XXX in the presence of acetic acid at an elevated temperature, either under a conventional procedure or a microwave reactor. Alternatively, formation of 1,2,4-triazolopyridine IG may be obtained by reacting deXX with Ph3PCI2 in the presence of a base such as TEA or by other methods known to one of ordinary skill in the art.

An appropriate protecting group (PG) may be employed for the compounds and / or functional groups (e.g. R 1, R 1, R 1, R 1, R 1, R 2, R 2a, R 2b R 2a, R 3a, R 3b, R 4, R 5, Re, L and Li) described in the above schemes for better reaction compatibility. The protecting group, if present, may be removed to provide the desired compound. For further examples of protecting groups and conditions for their removal, see "Protevtive Groups in Organic Synthesis", Greene et al., John Wiley eSons Inc., 1991.

UTILITIES AND COMBINATIONS

A. Utilities

The compounds of the present invention have activity as inhibitors of the 11-beta-hydroxysteroid dehydrogenase type I enzyme, and therefore may be employed in the treatment of diseases associated with 11-beta-hydroxysteroid dehydrogenase type I activity. By inhibiting 11-beta-hydroxysteroid dehydrogenase dehydrogenase type I, the compounds of the present invention may preferably be employed to inhibit or modulate glucocorticoid production, thereby disrupting or modulating cortisone or cortisol production.

Accordingly, the compounds of the present invention may be administered to mammals, preferably humans, for the treatment of a variety of conditions and disorders, including, but not limited to, treating, preventing, or reducing the progression of diabetes. Related conditions, microvascular complications associated with diabetes, macrovascular complications associated with diabetes, cardiovascular diseases, Metabolic Syndrome and its component conditions, inflammatory diseases and other diseases. Therefore, it is believed that the compounds of the present invention may be employed in the prevention, inhibition, or treatment of diabetes, hyperglycemia, impaired glucose tolerance, insulin resistance, hyperinsulinemia, retinopathy, neuropathy, nephropathy, delayed wound healing, atherosclerosis and its sequelae (acute coronary syndrome, myocardial infarction, angina pectoris, peripheral vascular disease, intermittent claudication), abnormal cardiac function, myocardial ischemia, stroke, Metabolic Syndrome, hypertension, obesity, dyslipidemia, hyperlipidemia , hypertriglyceridemia, hypercholesterolaemia, low HDL, high LDL, noncardiac ischemia, infection, cancer, vascular restenosis, pancreatitis, neurodegenerative disease, delipid disorders, cognitive impairment and dementia, bone disease, HIV protease-associated iripodistrofia, glaucoma and inflammatory diseases such as rheumatoid arthritis and osteo arthritis.

Metabolic syndrome or "Syndrome X" is described in Ford, and others, J. Am. Med. Assoc. 2002, 287, 356-359 and Arbeeny, et al., Curr. Med.Chem. - Imm., Endoc. & Metab. Agents 2001, 1, 1-24.

B. Combinations

The present invention includes within its scope pharmaceutical compositions comprising as an active ingredient a therapeutically effective amount of at least one of the compounds of formula I alone or in combination with a pharmaceutical carrier or diluent. Optionally, compounds of the present invention may be employed alone, in combination with other compounds of the invention, or in common combination or more other therapeutic agent (s), for example an antidiabetic agent or other pharmaceutically active material. .

The compounds of the present invention may be employed in combination with other 11-beta-hydroxysteroid dehydrogenase type I inhibitors or one or more other suitable therapeutic agents useful in the treatment of the above disorders including: antidiabetic agents, antihyperglycemic agents, antihyperinsulinemic agents, anti-retinopathic agents, anti-neuropathic agents, antinephropathic agents, anti-atherosclerotic agents, anti-ischemic agents, antihypertensive agents, anti-obesity agents, antihyperlipidemic agents, antihypertriglyceremic agents, antihypertensive agents, anti-restenotic agents, anti-pancreatic agents, lipid lowering agents, appetite suppressants, memory enhancing agents, cognition enhancing agents and anti-inflammatory agents.

Examples of suitable antidiabetic agents for use in combination with the compounds of the present invention include insulin and insulin analogs: LysPro insulin, inhaled formulations comprising insulin; glucagon-like peptides; sulfonylureas and the like: chlorpropamide, glibenclamide, tolbutamide, tolazamide, acetoexamide, glipizide, glyburide, glimepiride, repaglinide, meglitinide; biguanides: metformin, phenformin, buformin; alpha2 and imidazoline antagonists: midaglizole, isaglidole, derigli-dol, idazoxane, efaroxane, fluparoxane; other insulin secretagogues: II-nogliride, insulinotropin, exendin-4, BTS-67582, A-4166; thiazolidinediones: ciglitazone, pioglitazone, troglitazone, rosiglitazone; PPAR-gamma agonists; PPAR-alpha agonists; dual PPAR alpha / gamma agonists; SGLT2 inhibitors; dipeptidyl peptidase IV inhibitors (DPP4); glucagon-like peptide 1 receptor (GLP-1) agonists; aldose inhibitors is reduced; RXR agonists: JTT-501, MCC-555, MX-6054, DRF2593, GI-262570, KRP-297, LG100268; fatty acid oxidation inhibitors: clomoxir, etho-moxir; α-glucosidase inhibitors: precose, acarbose, miglitol, emiglitate, voglibose, MDL-25,637, camiglibose, MDL-73,945; beta agonists: BRL35135, BRL 37344, Ro 16-8714, ICI D7114, CL 316.243, TAK-667, AZ40140; phosphodiesterase inhibitors, both cAMP and cGMP type: sildenafil, L686398: L-386.398; amylin antagonists: pranlintide, AC-137; lipoxygenase inhibitors: masoprocal; Somatostatin analogs: BM-23014, seglitide, octreotide; glucagon antagonists: BAY 276-9955; insulin signaling agonists, insulin mimetics, PTP1B inhibitors: L-783281, TERI7411, TER17529; gluconeogenesis inhibitors: GP3034; somatostatin analogs and antagonists; antilipolytic agents: nicotinic acid, acipimox, WAG 994; glucose transport stimulating agents: BM-130795; glucose synthase kinase inhibitors: lithium chloride, CT98014, CT98023; and galanin receptor agonists.

Other suitable thiazolidinediones include Mitsu-bishi MCC-555 (described in US Patent No. 5,594,016), Glaxo-Wellcome GL-262570, englitazone (CP-68722, Pfizer), or darglitazone (CP-86325, Pfi-zer) , isaglitazone (MIT / J & J), JTT-501 (JPNT / P & U), L-895645 (Merck), R-119702 (Sankyo / WL), NN-2344 (Dr. Reddy / NN), or YM-440 (Yamanouchi ).

Suitable PPAR alpha / gamma dual agonists include AR-H039242 (Astra / Zeneca), GW-409544 (Glaxo-Wellcome), KRP297 (KyorinMerck), as well as those described by Murakami et al., "A Novel Insu-Iin Sensitizer Acts As the Coligand for Peroxisome Proliferation - ActivatedReceptor Alpha (PPAR alpha) and PPAR gamma; Effect of PPAR alpha Activation on Abnormal Lipid Metabolism in Liver of Zueker Fatty Rats ", Diabetes47, 1841-1847 (1998), and WO 01/21602, the description of which is incorporated herein by reference, employing dosages as set forth herein, whose preferred designated compounds are preferred for use herein.

Suitable alpha2 antagonists also include those described in WO 00/59506, employing dosages set forth herein.

Suitable SGLT2 inhibitors include T-1095, florizine, WAY-123783, and those described in WO 01/27128.

Suitable DPP4 inhibitors include saxagliptan, sitaglipta-na, vildagliptana, and denagliptana.

Suitable aldose reductase inhibitors include those described in WO 99/26659.

Suitable meglitinides include nateglinide (Novartis) or KAD1229 (PF / Kissei).

Examples of glucagon-like peptide 1 receptor (GLP-1) agonists include Exenatide (Byetta®), NN2211 (Liraglutide, Novo Nor-disk), AVE0010 (Sanofi-Aventis), R1583 (Roche / lpsen), SUN E7001 ( Daii-chi / Santory), GSK-716155 (GSK / Human Genome Sciences) and Exendin-4 (PC-DAC®).

Other antidiabetic agents that may be employed in combination with compounds of the invention include ergoset and D-chiroinositol.

Suitable anti-ischemic agents include, but are not limited to, those described in the Physician's Desk Reference and inhibitors of HE, including those described in WO 99/43663.

Examples of suitable lipid lowering agents for use in combination with the compounds of the present invention include one or more MTP inhibitors, HMG CoA reductase inhibitors, squalene synthetase inhibitors, fibric acid derivatives, ACAT inhibitors, lipoxygenase inhibitors, cholesterol absorption, deco-transporter Na + ileal / bile acid inhibitors, LDL1 receptor over-regulators of bile acid sequestrants, cholesterol ester transfer protein inhibitors (eg CP-529414 (Pfizer)), and / or nicotinic acid and derivatives thereof.

MTP inhibitors which may be employed as described above include those described in US Patent No. 5,595,872, US Patent No. 5,739,135, US Patent No. 5,712,279, US Patent No. 5,760,246, US Patent No. 5,827,875, US Patent No. 5,885,983, and US Patent No. 95,962,440.

HMG CoA reductase inhibitors that may be employed in combination with one or more compounds of formula I include me-vastatin and related compounds, as described in US Patent No. 93,983,404, Iovastatin (mevinolin) and related compounds, as described by Descripone. No. 4,231,938, pravastatin, and related compounds, as described in US Patent No. 4,346,227, simvastatin, and related compounds, as described in US Patent Nos. 4,448,784 and 4,450,171. Other HMG CoA reductase inhibitors that may be employed herein include, but are not limited to, fluvastatin, described in U.S. Patent No. 5,354,772; cerivastatin as described in U.S. Pat. 5,006,530 and 5,177,080; atorvastatin as described in U.S. Patent Nos. 4,681,893, 5,273,995, 5,385,929 and 5,686,104; atavastatin (Nissan / SankyO nisvastatin (NK-104)), as described in U.S. Patent No. 5,011,930; visastatin (Shionogi-Astra / Zeneca (ZD-4522)) as described in U.S. Patent No. 5,260,440.

Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, atavastatin, and ZD-4522.

Fibric acid derivatives that may be employed in combination with one or more compounds of formula I include fenofibrate, genfibrozil, clofibrate, bezafibrate, ciprofibrate, clinofibrate, and the like, pro-bucol, and related compounds, as described in US Patent No. 3. 674,836, fenofibrate and genfibrozil being preferred, bile acid sequestrants such as cholestyramine, colestipol and DEAE-Sephadex (Secho-lex®, Policexide®), as well as Iipostabila (Rhone-Poulenc), Eisai E-5050 (a N-substituted ethanolamine derivative), imanixyl (ENXADA-402), tetrahydro-lipstatin (THL), istigmastanylphosphorylcholine (SPC, Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulene derivative), melinamide (Sumitomo), 58-035, American Cyanamid CL-277,082 and CL-283,546 (disubstituted urea derivatives), nicotinic acid, acipimox, acifran, neomycin, p-aminosalicylic acid, aspirin, po-li (diallyl methylamine) derivatives as described in the patent No. 4,759,923, quaternary pol (diallyldimethylammonium chloride) diamine chloride and ionenes, as described in U.S. Patent No. 4,027,009, and other known serum cholesterol lowering agents.

ACAT inhibitors that may be employed in combination with one or more compounds of formula I include those described in Drugs of the Future 24, 9-15 (1999), (Avasimibe); "The ACAT inhibitor, CI-1011 is effective in the prevention and regression of aortic fatty acids in hamsters", Nicolosi et al., Atherosclerosis (Shannon, Irei). (1998), 137 (1), 77-85; "The pharmacological profile of FCE 27677: a novel ACATinhibitor with potent hypolipidemic activity mediated by selective suppression of the hepatic secretion of ApoBI O-containing lipoprotein", Ghiselli, Giancar-lo, Cardiovasc. Drug Rev. (1998), 16 (1), 16-30; "RP 73163: the bioavailablealkylsulfinyl-diphenylimidazole ACAT inhibitor", Smith, C., et al., Bioorg.Med. Chem. Lett. (1996), 6 (1), 47-50; "ACAT inhibitors: physiologic mechanisms for hypolipidemic and anti-atherosclerotic activities in experimental animals", Krause et al., Editor (s): Ruffolo, Robert R., Jr .; Hollinger, Mannfred A., Inflammation: Mediators Pathways (1995), 173-98, Publisher: CRC, Boca Raton, Fla .; "ACAT inhibitors: potential anti-atherosclerotic a-gents", Sliskovic et al., Curr. Med. Chem. (1994), 1 (3), 204-25; "Inhibitorsof acyl-CoA: cholesterol O-acyl transferase (ACAT) as hypocholesterolemicagents. 6. The first water-soluble ACAT inhibitor with lipid-regulating activity. Inhibitors of acyl-CoA: cholesterol acyltransferase (ACAT). 7. Development of a series of substituted N-phenyl-N '- [(1-phenylcyclopentyl) methyl] ureas withenhanced hypocholesterolemic activity ", Stout et al., Chemtracts: Org.Chem. (1995), 8 (6), 359-62, or TS-962 (Taisho Pharmaceutical Co. Ltd.).

The hypolipidemic agent may be an LDL receptor activity over-regulator such as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly).

Examples of suitable cholesterol absorption inhibitors for use in combination with the compounds of the invention include eze-thymib (Zetia®).

Examples of suitable Na + ileal / debile acid co-transporter inhibitors for use in combination with the compounds of the invention include compounds as described in Drugs of the Future, 24, 425-430 (1999).

Lipoxygenase inhibitors which may be employed in combination with one or more compounds of formula I include 15-lipoxygenase (15-LO) inhibitors, such as benzimidazole derivatives, as described in WO 97/12615, 15-LO inhibitors, such as described in WO97 / 12613, isothiazolones, as described in WO 96/38144, and 15-LO inhibitors, as described by Sendobry et al. "Attenuation of diet-induced atherosclerosis in rabbits with a highly selective 15-lipoxygenase inhibitor Iacking significant antioxidant properties "Brit. J. Pharmacology (1997) 120, 1199-1206, and Cornicelli et al., "15-Lipoxygenase and its Inhibition: A Novel Therapeutic Target for Vascular Disease", Current Pharmaceutical Design, 1999, 5, 11-20.

Examples of suitable antihypertensive agents for use in combination with the compounds of the present invention include beta-adrenergic blockers, calcium channel blockers (type L and type T; for example diltiazem, verapamil, nifedipine, amlodipine and mibefradil) , dimethyls (e.g. chlorothiazide, hydrochlorothiazide, flumetiazide, hydroflume-thiazide, bendroflumetiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrinic acid trichrinaphene, chlortalidone, furanemide, sporoethane, trisloride derenin inhibitors (e.g. aliskiren), ACE inhibitors (e.g. captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, chi-napril, ramipril, lisinopril), AT-1 receptor antagonists (e.g. , losartan, irbesartan, valsartan), ET receptor antagonists (e.g., sitaxsentan, atrsentan, and compounds described in US Patent Nos. 5,612,359 and Dual ET / AII antagonist (e.g., compounds described in WO 00/01389), neutral endopeptidase inhibitors (NEP) 1 vasopepidase inhibitors (dual NEP-ACE inhibitors) (e.g. , omapatrilate and gemopatrilate), and nitrates.

Examples of suitable anti-obesity agents for use in combination with the compounds of the present invention include an inverse cannabinoid receptor 1 antagonist or antagonist, a beta3 adrenergic agonist, a lipase inhibitor, a serotonin reuptake inhibitor (and dopamine), a beta thyroid receptor drug, and / or anorectic agent.

Inverse agonists and cannabinoid receptor 1 antagonists, which may optionally be employed in combination with compounds of the present invention include rimonabant, SLV 319, CP-945598 (Pfizer), SR-147778 (Sanofi-Aventis), MK0364 (Merck) and those discussed. in DLHertzog, Expert Opin. The R. Patents 2004, 14, 1435-1452.

Beta 3 adrenergic agonists which may optionally be employed in combination with compounds of the present invention include AJ9677 (Takeda / Dainippon), L750355 (Merck), or CP331648 (Pfizer), or other known beta 3 agonists, as described in US Patent Nos. 5,541,204 , 5,770,615, 5,491,134, 5,776,983, and 5,488,064, with AJ9677, L750,355, and CP331648 being preferred.

Examples of lipase inhibitors which may optionally be employed in combination with compounds of the present invention include orlistat or ATL-962 (Alizyme), with orlistat being preferred.

The serotonin (and do-pamine) uptake inhibitor and / or modulator that may be optionally employed in combination with a compound of formula I may be sibutramine, topiramate (Johnson & John-son), APD-356 (Arena) or axoquine (Regeneron), with sibutramine and APD-356 being preferred. Examples of thyroid beta receptor compounds that may optionally be employed in combination with compounds of the present invention include thyroid receptor ligands, such as those described in WO97 / 21993 (U. Cal SF), WO99 / 00353 (KaroBio), and WO00 / 039077 (KaroBio), with compounds of the KaroBio applications being preferred.

The anorectic agent which may optionally be employed in combination with compounds of the present invention includes dexamphetamine, phenamine, phenylpropanolamine, or mazindole, with dexamphetamine being preferred.

Other compounds which may be employed in combination with the compounds of the present invention include CCK receptor agonists (e.g. SR-27895B); MCHR1 antagonist (e.g. GSK856464); galanin receptor antagonists; MCR-4 antagonists (e.g., HP-228); leptin mimetics; urocortin mimetics, CRF antagonists, and CRF binding proteins (e.g., RU-486, urocortin).

In addition, the compounds of the present invention may be employed in combination with HIV protease inhibitors, including but not limited to Reyataz® and Kaletra®.

Examples of suitable memory enhancing agents, anti-depletion agents, or cognition enhancing agents for use in combination with the compounds of the present invention include, but are not limited to, donepezil, rivastigmine, galantamine, memantine, tacrine, metrifonate, muscarine. , xanomelin, deprenyl and physostigmine.

Examples of suitable anti-inflammatory agents for use in combination with the compounds of the present invention include, but are not limited to, prednisone, acetaminophen, aspirin, codeine, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, pyroxycam, a steroidal analgesic. , sufentanil, sunlindac, interferon alfa, prednisone, methylprednisolone, dexametazone, flucatisone, betamethasone, hydrocortisone and beclomethasone.

The aforementioned patents and patent applications are incorporated herein by reference.

The other therapeutic agents mentioned above, when employed in combination with the compounds of the present invention may be employed, for example, in those amounts indicated in the Physician'sDesk Reference, as in the patents set forth above, or as otherwise determined by one of ordinary skill in the art. .

The compounds of formula I may be administered for any of the uses described herein by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques (for example, as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the unsalted membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally as in the form of suppositories; unit dosage formulations containing non-toxic pharmaceutically acceptable carriers or diluents.

In carrying out the method of the invention for treating diabetes and related diseases, a pharmaceutical composition will be employed containing the compounds of formula I, with or without other antidiabetic agent (s) and / or agent (s). ) antihyperlipidemic and / or other therapeutic agents in combination with a pharmaceutical carrier or diluent. The pharmaceutical composition may be formulated using conventional solid or liquid carriers or diluents and pharmaceutical additives of a type suitable for the desired mode of administration, such as pharmaceutically acceptable excipients, binders, and the like. The compounds may be administered to a mammalian patient, including humans, monkeys, dogs, etc. by an oral routine, for example, in the form of tablets, capsules, beads, granules or powders. The adult dose is preferably between 1 and 2,000 mg per day, which may be administered as a single dose or as individual doses of 1 to 4 times per day.

A typical capsule for oral administration contains compounds of structure I (250 mg), lactose (75 mg), and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packaged in a No. 1 gelatin capsule.

A typical injectable preparation is produced by aseptically placing 250 mg of the compounds of structure I in a vial, freeze drying and sealing. For use, the contents of the vial are mixed with 2 mL of physiological saline to produce an injectable preparation.

TEST (S) ON THE ACTIVITY OF 11-BETA HYDROXYESTEROID DEHYDROGENASE

In vitro inhibition of recombinant human beta-HSD1 was determined as follows.

Recombinant human beta-HSD1 was stably expressed in HEK 293 EBNA cells. Cells were cultured in DMEM (high glucose) containing non-essential amino acids from MEM, L-glutamine, hygromycin B (200 µg / ml), and G418 (200 µg / ml). µg / ml). The cell pellets were homogenized, and the microsomic fraction was obtained by differential centrifugation. 11beta-HSD1 overexpressed microsomes were employed as the enzyme source for the Scintillation Proximity Assay (SPA). Test compounds at the desired concentration were incubated at room temperature with 12.5 μg microsomal enzyme, 250 nM of [3H] -cortisone, 500 μΜ NADPH, 50 mM MES, pH 6.5, and 5 and 5 EDTA mM in 96-well OptiPIates. The reaction was terminated with the addition of 1 mM 18p-glycerenic acid. SPA reagent mixture (IgGanticoelho YSi, 50 mM Tris anti-cortisol antibody, pH 8.0 containing 1% CHAPS and 1% glycerol) was added and the reaction was again incubated at room temperature overnight and counted. TopCount. IC50 (compound concentration required for 50% inhibition of decortisol formation) was determined using XLfit.

In general, preferred compounds of the present invention, such as particular compounds described in the following examples have been identified, to inhibit the catalytic activity of 11-beta-hydroxysteroid dehydrogenase type I at concentrations equivalent to or more potent than 10 μΜ, preferably 5 µM. μΜ, more preferably 3 μΜ, thereby demonstrating the compounds of the present invention as especially effective inhibitors of 11-beta-hydroxysteroid dehydrogenase type I. Potencies may be calculated and expressed either as inhibition constants (Ki values) or as IC50 values (inhibitory concentration 50%), and refer to measurement activity using the assay system described above.

EXAMPLES

The following Working Examples serve to further illustrate, but are not limited to, some of the preferred embodiments of the present invention.

GENERAL

The term HPLC refers to Shimadzu high performance liquid chromatography using one of the following methods:

Method A: YMC or Phenomenex C18 5 micron 4.6 X 50 mm column using a 4 minute gradient of 0 to 100% solvent B [90% Me-OH: 10% H2 O: 0.2% H3PO4] and 100 to 0% solvent A [10% MeOH: 90% H2O: 0.2% H3PO4] with a flow rate of 4 mL / min and a 1 minute maintenance, an ultra detector -violet (UV) adjusted to 220 nm.

Method B: Phenomenex S5 ODS 4.6 χ 30 mm column, 0 to 100% B / A gradient elution over 2 minutes (solvent A = 10% MeOH / H2 O containing 0.1% TFA, solvent B = 90% MeOH / H2 O containing 0.1% TFA), flow rate 5 mL / min, UV detection at 220 nm.

Method C: YMC S7 ODS 3.0 χ 50 mm column, gradient elution 0 to 100% B / A over 2 minutes (solvent A = 10% MeOH / H2 O containing 0.1% TFA, solvent B = 90% MeOH / H2 O containing 0.1% TFA), flow rate 5 mL / min, UV detection at 220 nm.

The term prep HPLC refers to an automated Shimadzu HPLC system employing a mixture of solvent A (10% MeOH / 90% H2 O / 0.2% TFA) and solvent B (90% MeOH / 10% H2 O / 0.2% TFA). Preparative columns were packed with YMC or Phenomenex ODS C18 5 micron resin or equivalent.

The following abbreviations are used in the Examples and elsewhere:

Ph = phenyl

Bn = benzyl

i-Bu = iso-butyl

Me = methyl

Et = ethyl

Pr = propyl

Bu = butyl

AIBN = 2,2'-Azobisisobutyronitrile

Boc or BOC = tert-butoxycarbonyl

Cbz = carbobenzyloxy or carbobenzoxy or benzyloxycarbonyl

DCM = dichloromethane

DEAD = AzodicarboxyIatodedietiA

DIAD = Diisopropyl azodicarboxylate

DIEA = N, N-diisopropylethylamine

DMA = N, N-dimethylacetylamide

DMF = N, N-dimethylformamide

DMSO = dimethyl sulfoxide

EtOAc = ethyl acetate

EDAC = 3-ethyl-34-dimethylamino) propyl carbodiimide hydrochloride (or 1 - [(3- (dimethyl) amino) propyl]) -3-ethylcarbodiimide hydrochloride)

FMOC = fluorenylmethoxycarbonyl

HOAc or AcOH = acetic acid

HOAT = 1-hydroxy-7-azabenzotriazole

HOBT = 1-hydroxybenzotriazole

LAH = lithium aluminum hydride

mCPBA = 3-chloroperoxybenzoic acid

NMM = N-methyl morpholine

NBS = N-Bromosucinimide

n-BuLi = n-butyllithiumOxone® = Monopersulfate

Pd / C = palladium on carbon

PtO2 = platinum oxide

PyBOP reagent = benzotriazol-1-yloxy tripyrrolidine phosphonium hexafluorophosphate

SOCI2 = Thionyl chloride

TBAF = tetrabutylammonium fluoride

TBS = tert-Butyldimethylsilyl

TMS = trimethylsilyl

ASD = triethylamine

TFA = trifluoroacetic acid

THF = tetrahydrofuran

equiv = equivalent (s)

min = minute (s)

h or hr = hour (s)

L = liter

mL = milliliter

μΙ_ = microliter

g = gram (s)

mg = milligram (s)

mol = mole (s)

mmol = millimole (s)

meq = milliequivalent

RT = room temperature

sat or sat'd = saturated

watery

TLC = thin layer chromatography

HPLC = high performance liquid chromatography

HPLC tA = HPLC retention time

LC / MS = high performance liquid chromatography / mass spectrometry

MS or Mass Spec = mass spectrometry NMR = nuclear magnetic resonance

mp = melting point

EXAMPLE 1

3-Cycloeptyl-8 - ((2,6-dichlorophenoxy) methyl) - [1,2,4] triazolo [4,3-a] pyridine

<formula> formula see original document page 55 </formula>

Compound 1 A. 1- (3 - ((tert-Butyldimethylsilyloxy) methyl) pyridin-2-yl) hydrazine

<formula> formula see original document page 55 </formula>

To a solution of (2-chloropyridin-3-yl) methanol (3.4 g, 23.7 mmol) in 50 mL of dichloromethane was added imidazole (2.4 g, 35.3 mmol) tert-butyldimethylsilylchloride ( 4.3 g, 28.5 mmols) at room temperature. The mixture was stirred at room temperature for 60 minutes, and then diluted with 100 mL of hexanes. The white solid was filtered, and the filtrate was concentrated under reduced pressure. The additional solid was removed by trituration with 5% ethyl acetate in hexanes to afford a clear a-yellow oil. The light yellow oil was dissolved in 40 mL of dioxane and then hydrazine (7.5 mL, 238.7 mmol) was added. The resulting mixture was heated at reflux for 36 hours. After this time, the mixture was cooled to room temperature, and the solvent was removed in vacuo to provide a residue. The residue was diluted with ethyl acetate, washed with water, dried over Na2 SO4 and concentrated under reduced pressure to afford the title compound (4.7 g, 78%) as a brown oil. HPLC tA (Method A): 2.42 minutes. LC / MS (m / z) = 254 (M + H) +.

Compound 1B. N- (3 - ((tert-Butyldimethylsilyloxy) methyl) pyridin-2-yl) cycloeptanecarbohydrazide

<formula> formula see original document page 55 </formula> To a solution of cycloeptanecarboxylic acid (2.69 g, 18.9mmols) in 20 mL of anhydrous THF was added NMM (2.8 mL, 25.2mmols) followed by by iso-butyl chloroformate (2.5 mL, 18.9 mmols) to 0O C under nitrogen. The reaction was stirred at 0 ° C for 30 minutes. A solution of compound 1A (1.6 g, 6.3 mmol) in 15 mL of THF was added, and stirring was continued at 0 ° C at room temperature for 3 hours. Sandation was quenched with water, and the solvent was removed in vacuo to provide a residue. The residue was diluted with ethyl acetate, washed with water, dried over Na2SÜ4 and concentrated to provide crude material. The crude material was purified by silica gel chromatography (10-30% ethyl acetate in hexanes) to afford the title compound (810 mg, 34%) as an oil. HPLC tA (Method A): 3.30 minutes. LC / MS (m / z) = 378 (M + H) +.

Compound 1C. 8 - ((tert-Butyldimethylsilyloxy) methyl) -3-cycloeptyl [1,2,4] triazolo [4,3-a] pyridine.

<formula> formula see original document page 56 </formula>

To a solution of compound 1B (810 mg, 2.15 mmol) in 15 mL of anhydrous THF was added DIEA (3 mL, 17.2 mmol) at -78 ° C. The reaction mixture was stirred for 15 minutes. Dichlorotriphenylphosphorane (2.15 g, 6.45 mmol) was then added at -78 ° C under nitrogen, and the reaction mixture was stirred at room temperature overnight to provide a solid. The solid was filtered, washed with THF, and the combined filtrate was vacuum concentrated to provide a residue. The residue was diluted with ethyl acetate, washed with water, dried over Na2 SO4 and concentrated to provide crude material. The crude material was purified by silica gel chromatography (10-30% ethyl acetate in hexanes) to afford the title compound (601 mg, 78%) as a yellow oil. HPLC tA (Method A): 4.05 minutes. LC / MS (m / z) = 360 (M + H) +.

Compound 1 D. (3-Cycloeptyl [1,2,4] triazolo [4,3-a] pyridin-8-yl) methanol <formula> formula see original document page 57 </formula>

To a solution of compound 1C (601 mg, 1.67 mmol) in 5 mL of anhydrous THF was added a solution of TBAF (3.4 mL, 3.4 mmol, 1 M in THF) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After this time, the solvent was removed. The resulting residue was diluted with ethyl acetate, washed with water, dried over Na 2 SO 4 and concentrated to provide crude material. The crude material was purified by silica gel chromatography (5-10% methanol in ethyl acetate) to afford the title compound (389 mg, 95%) as a white flake. HPLC tA (Method A): 1.80 min. LC / MS (m / z) = 246 (M + H) +.

Example 1

To a solution of compound 1D (30 mg, 0.12 mmol) in 5 mL of anhydrous THF was added 2,6-dichlorophenol (30 mg, 0.18 mmol), triphenylphosphine (48 mg, 0.18 mmol) and DIAD (37 mg, 0.18 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, and then concentrated in vacuo to afford a residue. The residue was diluted with ethyl acetate, washed with water, dried over Na 2 SO 4 and concentrated to afford the crude product. The crude product was purified by silica gel chromatography (20 to 30% ethyl acetate in hexanes) to afford Example 1 as a white solid (42 mg, 89%). HPLC tA (Method A): 3.69 minutes. LC / MS (m / z) = 390 (M + H) +. 1 H NMR: δ 7.79 (dd, J = 1.7 Hz, 1H), 7.60 (dd, J = 1.7 Hz, 1H), 7.27 (d, J = 8 Hz, 2H), 6.96 - 7.00 (m, 1H), 6.84 (t, J = 7 Hz, 1H), 5.47 (s, 2H), 3.16 - 3.29 (m, 1H), 1 .92 - 2.12 (m, 4H), 1.76 - 1.82 (m, 2H), 1.51 - 1.70 (m, 6H).

EXAMPLE 2

3-Cycloeptyl-8 - ((2,6-dichlorophenylthio) methyl) - [1,2,4] triazolo [4,3-a] pyridine.

<formula> formula see original document page 57 </formula> A solution of compound 1D (140 mg, 0.57 mmol) in 15 mL of dichloromethane was treated with SOCI2 (0.166 mL, 2.28 mmol) at room temperature. The reaction mixture was stirred for 2 hours at room temperature. After this time, the solvent was evaporated under reduced pressure to afford a white powder. The white powder was suspended in 20 mL of dichloromethane, treated with DIEA (0.478 mL, 2.85 mmol) followed by 2,6-dichlorobenzenethiol (0.206 g, 1.15 mmol) at room temperature and then stirred for 2 hours at room temperature. The resulting mixture was concentrated and purified by silica gel chromatography (20-50% ethyl acetate in hexanes) to afford Example 2 as a colorless oil (212 mg, 91%). HPLC tA (Method A): 3.44 minutes. LC / MS (m / z) = 406 (M + H) +. 1H NMR: δ 7.69 (d, J = 7 Hz, 1H), 7.25 (d, J = 8Hz, 2H), 7.08 (t, J = 8Hz, 1H), 6.65 (d , J = 7 Hz, 1H), 6.53 (t, J = 7 Hz, 1H), 4.40 (s, 2H), 3.12-3.24 (m, 1H), 1.92 - 2 0.10 (m, 4H), 1.72-1.89 (m, 2H), 1.48-1.72 (m, 6H).

EXAMPLE 3

3-Cycloeptyl-8 - ((2,6-dichlorophenylsulfonyl) methyl) - [1,2,4] triazolo [4,3-a] pyridine.

<formula> formula see original document page 61 </formula>

A solution of Example 2 (110 mg, 0.271 mmol) in 20 mL of dichloromethane was treated with mCPBA (390 mg, 1.35 mmol) at room temperature for 4 hours. After this time, the reaction mixture was analyzed by LCMS1 which indicated the presence of sulfoxide. Additional mCPBA (156 mg, 0.542 mmol) was added. At the end of the addition, the reaction mixture was stirred for an additional 2 hours. At the end of this period, the reaction mixture was diluted with dichloromethane, washed with 1N NaOH, brine and water, dried over MgSO4, and concentrated to provide crude product. The crude product was purified by silica gel chromatography (50% ethyl acetate in hexanes) to afford Example 3 as a light brown thick oil (57.5 mg, 48%). HPLC tA (Method A): 2.99 minutes. LC / MS (m / z) = 438 (M + H) +. 1H NMR: δ 7.78 (dd, J = 1.7 Hz, 1H), 7.39 (dd, J = 1.7 Hz, 1H), 7.19 - 7.29 (m, 3H), 6 , 78 (t, J = 7 Hz 1H), 5.08 (s, 2Η), 3.07 - 3.17 (m, 1Η), 1.92 - 2.02 (m, 4Η), 1.72 - 1.82 (m, 2Η), 1.42-1.72 (m, 6H).

EXAMPLE 4

8 - ((2,6-Dichlorobenzyloxy) methyl) -3-cycloeptyl [1,2,4] triazolo [4,3-a] pyridine

<formula> formula see original document page 59 </formula>

To a solution of compound 1D (50 mg, 0.204 mmol) in 1 mL of DMF was added sodium hydride (8.2 mg, 0.204 mmol, 60% in mineral oil) at room temperature. After stirring for 15 minutes at room temperature, the reaction mixture was cooled to 0 ° C and 2,6-dichlorobenzyl bromide (49 mg, 0.204 mmol) was added. At the end of the addition, the reaction mixture was stirred at 0 ° C at room temperature for 1.5 hours, quenched with water, and then extracted with ethyl acetate to provide the crude product. The crude product was purified by silica gel chromatography (30 to 50% ethyl acetate in hexanes) to afford Example 4 as a yellow oil (46 mg, 56%). HPLC tA (Method A):

3.53 minutes. LC / MS (m / z) = 404 (M + H) 1 H NMR: δ 7.81 (dd, J = 1.7 Hz, 1H), 7.39 (dd, J = 1.7 Hz, 1H ), 7.35 - 7.37 (m, 2H), 7.25 - 7.21 (m, 1H), 6.83 (t, J = 7 Hz, 1H), 5.14 (s, 2H) , 5.02 (s, 2H), 3.20 - 3.35 (m, 1H), 2.01 - 2.21 (m, 4H), 1.84 - 2.00 (m, 2H), 1 .58 - 1.82 (m, 6H).

EXAMPLE 5

3-Chloro-N '- ((3-cycloeptyl [1,2,4] triazolo [4,3-a] pyridin-8-yl) methyl) -2-methylbenzenesulfonamide.

<formula> formula see original document page 59 </formula>

Compound 5A. (3-Cycloeptyl [1,2,4] triazolo [4,3-a] pyridin-8-yl) methanamine.

<formula> formula see original document page 59 </formula>

To a solution of compound 1D (150 mg, 0.611 mmol) in 10 mL of dichloromethane was added DIEA (0.425 mL, 3.055 mmols) and methanesulfonyl chloride (140 mg, 1.22 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C at room temperature for 2 hours. After this time, the reaction mixture was diluted with dichloromethane, washed with brine and water, dried over MgSO4, and concentrated under reduced pressure to afford a residue. The residue was dissolved in 5 mL of DMF, and then sodium acetate (60 mg, 0.817 mmol) was added. The resulting mixture was heated at 50 ° C for 1 hour. After this time, the reaction mixture was diluted with ethyl acetate, washed with brine and water, dried over MgSO 4, filtered and concentrated to afford the azide intermediate. The azide intermediate was dissolved in 15 mL of THF and 3 mL of water. Polymer-bound PPh 3 (3 mmol / g, 500 mg, 1.53 mmol) was added and the resulting mixture was heated at 50 ° C for 1 hour. The resulting solid was filtered and the solvent was removed from the filtrate to afford the title compound (120 mg, 80%) as a yellow oil. HPLC tA (Method A): 1.58 minutes.

LC / MS (m / z) = 245 (M + H) +.

Example 5

To a solution of compound 5A (35 mg, 0.143 mmol) in 3 mL dichloromethane was added TEA (0.1 mL, 0.715 mmol) and 3-chloro-2-methylbenzene-1-sulfonyl chloride (96.8 mg, 0.430 mmol) at room temperature. The reaction mixture was stirred for 2 hours at room temperature. At the end of this period, the reaction mixture was concentrated, diluted with ethyl acetate, washed with 1 N NaOH, brine and water, dried over MgSO4 and concentrated to provide crude product. The crude product was purified by silica gel chromatography employing 20-100% ethyl deacetate in hexanes to provide Example 5 as a pale yellow powder (21.4 mg, 35%). HPLC tA (Method A): 3.31 minutes. LC / MS (m / z) = 433 (M + H) +. 1H NMR: δ 7.82 (d, J = 8Hz, 1H), 7.71 (d, J = 7Hz, 1H), 7.38 (d, J = 8Hz, 1H), 7.10 (t , J = 8 Hz, 1H), 6.93 (d, J = 7 Hz, 1H), 6.51 - 6.72 (m, 2H), 4.54 (d, J = 6 Hz, 2H), 3.1 - 3.3 (m, 1H), 2.52 (s, 3H), 1.52 - 2.22 (m, 12H).

EXAMPLE 6

3- (Azepan-1-yl) -8 - ((2,6-dichlorophenoxy) methyl) - [1,2,4] triazolo [4,3-a] pyridine Compound 6A. Azepane-1-carbonyl chloride

<formula> formula see original document page 61 </formula>

To a solution of azepane (2 g, 20.2 mmol) in 30 mL of anhydrous toluene was added DIEA (3.5 mL, 20.0 mmol) and pyridine (1.63 mL, 20.2 mmol). The mixture was cooled to -10 ° C under nitrogen. Once at the prescribed temperature, carbon dioxide gas was bubbled through the solution for 30 minutes, and then a solution of thionyl chloride (1.74 mL, 24.0 mmols) in 10 mL of toluene was added. added at -10 ° C. Upon completion of the addition, the reaction mixture was stirred for 1 hour while maintaining the temperature under 10 ° C. The reaction mixture was then diluted with ethyl acetate, washed with cold 0.5 N HCl solution and brine, dried over Na 2 SO 4, and concentrated to yield the title compound (2.76 g, 85%). as a light yellow oil.

Compound 6B. N ^-S-tert-Butyldimethylsilyloxymethylpyridin-10-azepane-1-carbidrazide.

<formula> formula see original document page 61 </formula>

To a solution of compound 1A (1.7 g, 6.7 mmol) in 10 mL of dichloromethane was added DIEA (2.33 mL, 13.4 mmol) and compound 6A (1.3 g, 8.0 mmol) to room temperature. The reaction mixture was heated at 45 ° C for 6 hours, cooled to room temperature and quenched with water. After dichloromethane was removed by rotavap, the reaction mixture was diluted with ethyl acetate, washed with water, dried over Na2 SO4 and concentrated to give a residue. The residue was triturated with ethyl acetate and hexanes to yield the title (2.1 g, 83%) as a white solid. HPLC tA (Method A): 2.98 minutes. LC / MS (m / z) = 379 (M + H) +.

Compound 6C. 3- (Azepan-1-yl) -8- (chloromethyl) - [1,2,4] triazolo [4,3-a] pyridine <formula> formula see original document page 62 </formula>

To a solution of compound 6B (1.5 g, 4.0 mmol) in 10 mL of anhydrous toluene was added POCl 3 (0.73 mL, 8.0 mmol) at room temperature. The reaction mixture was heated at 70 ° C for 2 hours, cooled to room temperature and then quenched with water. The reaction mixture was diluted with ethyl acetate, washed with water, dried over Na 2 SO 4 and concentrated to provide crude material. The crude material was purified by silica gel chromatography (50 - 100% ethyl acetate in hexanes) to afford the title compound (307 mg, 29%) as a light yellow solid. HPLC tA (Method A): 1.98 min. LC / MS (m / z) = 265 (M + H) +.

Example 6

To a solution of 2,6-dichlorophenol (107 mg, 0.66 mmol) in 3 mL of anhydrous acetone was added potassium carbonate (114 mg, 0.82 mmol) and compounds 6C (145 mg, 0.55 mmol) to room temperature. Upon completion of the addition, the reaction mixture was heated at 60 ° C for 2 hours, cooled to room temperature and then quenched with water. The acetone was removed in vacuo, and the reaction mixture was diluted with ethyl acetate, washed with water, dried over Na 2 SO 4 and concentrated to provide crude product. The crude product was purified by silica gel chromatography (50% ethyl acetate in hexanes) to afford Example 6 as a white solid (185 mg, 86%). HPLC tA (Method A): 3.35 minutes.

LC / MS (m / z) = 391 (M + H) +. 1 H NMR: δ 7.77 (dd, J = 1.7 Hz, 1H), 7.60 (dd, J = 1.7 Hz, 1H), 7.31 (d, J = 8 Hz, 2H), 7.03 (t, J = 8Hz, 1H), 6.81 (t, J = 7Hz, 1H), 5.47 (s, 2H), 3.49 (t, J = 6Hz, 4H) , 1.83 - 1.91 (m, 4H), 1.71 - 1.78 (m, 4H).

EXAMPLE 7

8- (3-Chloro-2-methylphenoxy) -3-cycloeptyl [1,2,4] triazolo [4,3-a] pyridine. <formula> formula see original document page 63 </formula>

Compound 7A. 3- (3-Chloro-2-methylphenoxy) -2-fluoropyridine

<formula> formula see original document page 63 </formula>

3-Chloro-2-methylphenylboronic acid (2 g, 11.74 mmols), 2-fluoro-3-hydroxy pyridine (663 mg, 5.87 mmols), copper acetate (1.1 g, 5.87 mmols) , pyridine (2.4 mL, 29.35 mmols), and fres-cas activated 4A molecular sieves (7 g) were combined in 100 mL dichloromethane in a round deep flask equipped with a drying tube (air-connected) . The reaction mixture was stirred at room temperature overnight. At the end of this period, the solid was filtered, and the filtrate was concentrated under reduced pressure to provide the crude material. The crude material was purified by silica gel chromatography (5-10% ethyl acetate in hexanes) to afford compound 7A (1.08 g, 77%) as a white powder. HPLC at A: 3.61 minutes, LC / MS (m / z) = 238 (M + H) +.

7B. 1- (3- (3-Chloro-2-methylphenoxy) pyridin-2-yl) hydrazine.

<formula> formula see original document page 63 </formula>

To a solution of compound 7A (500 mg, 2.1 mmol) in 15 mL of dioxane was added anhydrous hydrazine (0.529 mL, 16.8 mmol). The reaction mixture was heated at 100 ° C for 3 hours. After this time, the reaction mixture was analyzed by LC / MS, which showed that the reaction was not completed. Additional hydrazine (0.529 mL, 16.8 mmol) was added, and the reaction mixture was heated at 100 ° C overnight. At the end of this period, the solvent was concentrated under reduced pressure to afford compound 7B (700 mg, 100%) as a white solid. HPLC tA: 1.89 minutes, LC / MS (m / z) = 250 (M + H) +.

Compound 7C. N '- (3- (3-Chloro-2-methylphenoxy) pyridin-2-yl) cycloeptanecarbohydrazide.

To a solution of cycloeptyl carboxylic acid (896 mg, 6.3 mmol) in 40 mL of anhydrous THF was added NMM (0.693 mL, 6.3 mmol) and isobutyl chloroformate (0.83 mL, 6.3 mmol) at 0 ° C. . The reaction mixture was stirred at 0 ° C for 30 minutes, and the resulting suspension was poured into a solution of compound IB (524 mg, 2.1 mmol) in 20 mL of THF at 0 ° C. The resulting mixture was stirred at 0 ° C for 1 hour, and the resulting solid was filtered. The filtrate was concentrated under reduced pressure to provide crude material. The crude material was purified by silica gel dechromatography (5-20% ethyl acetate in hexanes) to provide the title compound (800 mg, 92%) as a white powder, HPLC tA (Method A): 2.98 minutes LC / MS (m / z) = 374 (M + H) +.

Example 7

To a solution of compound 7C (700 mg, 1.87 mmol) in 20 mL of anhydrous THF was added DIEA (2.6 mL, 15 mmol) at -78 ° C. The reaction mixture was stirred at -78 ° C for 30 minutes and then dichlorotrife-nylphosphorane (2.06 g, 6.18 mmol) was added. The resulting mixture was stirred at -78 ° C at room temperature overnight. After this time, the resulting white solid was filtered, and the filtrate was concentrated under reduced pressure to provide crude product. Purification by silica gel chromatography (0-30% ethyl acetate in hexanes) provided Example 7 as a white powder (630 mg, 94%). HPLC tA (Method A): 3.63 minutes.

LC / MS (m / z) = 356 (M + H) +. 1H NMR: δ 7.64 (d, J = 7 Hz, 1H), 7.22 (d, J = 8Hz, 1H), 7.11 (t, J = 8Hz, 1H), 6.95 (d, J = 8Hz, 1H), 6.63 (t, J = 7Hz, 1H), 6.09 (d, J = 7Hz, 1H), 3.13-3.30 (m, 1H), 1 , 42-2.33 (m, 12H).

EXAMPLE 8

8- (3-Chloro-2-methylphenoxy) -3- (4-methoxybicyclo [2,2,2] octan-1-yl) - [1,2,4] triazolo [4,3-a] pyridine. formula> formula see original document page 65 </formula>

Compound 8A. N '- (3- (3-Chloro-2-methylphenoxy) pyridin-2-yl) -4-methoxybicyclo [2,2,2] octane-1-carbidrazide

<formula> formula see original document page 65 </formula>

To a stirred solution of 4-methoxybicyclo [2,2,2] octane-1-carboxylic acid (590 mg, 3.2 mmol; see Adcock and Abeywickrema, J., Org.Chem. 1982, 47, 2951-2957) in 8 mL of anhydrous THF was added NMM (0.423 mL, 3.8 mmol) and isobutyl chloroformate (0.50 mL, 3.8 mmol) at 0 ° C. The reaction was stirred at 0 ° C for 30 minutes, and then Compound 7B (800 mg, 3.2 mmol) was added at 0 ° C. The resulting mixture was stirred at 0 ° C for 10 minutes followed by 90 minutes at room temperature before quenching with water. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried over Na2 SO4 and concentrated. Purification through silica gel chromatography (30 - 60% ethyl acetate in hexanes) provided compounds 8A as a light yellow foam solid (840 mg, 63%). HPLC tA (Method A): 2.56 minutes. LC / MS (m / z) = 415 (M + H) +.

Example 8

To a suspension of compound 8A (420 mg, 1.0 mmol) in 5 mL of anhydrous toluene was added POCl 3 (0.275 mL, 3.0 mmol) at room temperature. The resulting solution was heated at 110 ° C for 3 hours, cooled to room temperature, and then quenched with water. After pH was adjusted to basic with NaOH, the mixture was extracted with ethyl acetate. The combined extracts were dried over Na 2 SO 4 and concentrated. Purification by silica gel chromatography (20-50% ethyl acetate in hexanes) provided Example 8 as a white solid (250 mg, 63%). HPLC tA (Method A): 3.32 minutes. LC / MS (m / z) = 398 (Μ + Η) +. 1H NMR (CDCl3): δ 7.89 (d, J = 7.0 Hz, 1Η), 7.29 (d, J = 8.3 Hz, 1,), 7.16 (t, J = 7, 9 Hz1 1 Η), 7.01 (d, J = 7.5 Hz, 1 Η), 6.58 (t, J = 7.5 Hz, 1 Η), 6.12 (d, J = 7, 5 Hz, 1 H), 3.23 (s, 3 H), 2.31 (t, J = 8.0 Hz, 6 H), 2.27 (s, 3 H), 1.86 (t, J = 8 .0 Hz, 6H).

EXAMPLES 9 AND 10

4- (8- (3-Chloro-2-methylphenoxy) - [1,2,4] triazolo [4,3-a] pyridin-3-yl) bicyclo [2,2,2] octan-1-ol and 4- (8- (3-Chloro-2-methylphenoxy) - [1,2,4] triazolo [4,3-a] pyridin-3-yl) bicyclo [2,2,2] octan-1- acetate ila respectively

<formula> formula see original document page 66 </formula>

To a suspension of Example 8 (290 mg, 0.73 mmol) in anhydrous acetic anhydride (1 mL, 10.6 mmol) was slowly added 48% aqueous HBr solution (0.7 mL, 6.2 mmol). . The reaction was heated to 100 ° C for 20 hours, and cooled to room temperature. It was diluted with ethyl comacetate, washed with 1N NaOH solution, dried over concentrated Na 2 SO 4. Purification by preparative HPLC afforded Example 9 (220 mg, 61%) and Example 10 (9 mg, 3%), both as TFA salt.

Example 9: HPLC tA (Method A): 3.07 minutes. LC / MS (m / z) = 384 (M + H) +.

1H NMR (CDCl3): δ 7.97 (d, J = 7.0 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.18 (t, J = 8.3 Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H), 6.76 (t, J = 7.2 Hz, 1H), 6.30 (d, J = 7.5 Hz, 1H), 2.32 (t, J = 7.9 Hz, 6H), 2.25 (s, 3H), 1.88 (t, J = 7.9 Hz, 6H).

Example 10: HPLC tA (Method A): 3.57 minutes. LC / MS (m / z) = 426 (M + H) + 1 H NMR (CDCl 3): δ 8.16 (d, J = 7.0 Hz, 1H), 7.33 (d, J = 7, 9 Hz, 1H), 7.19 (t, J = 7.9 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.87 (t, J = 7.0 Hz , 1H), 6.42 (d, J = 7.5 Hz, 1H), 2.29 - 2.35 (m, 6H), 2.24 (s, 3H), 2.18 - 2.22 ( m, 6H), 2.00 (s, 3H).

EXAMPLE 11

4- (8- (2-Chloro-5-methylphenoxy) - [1,2,4] triazolo [4,3-a] pyridin-3-yl) bicyclo [2,2,1] heptan-1-ol formula> formula see original document page 67 </formula>

Compound 11 A. 3-Bromo-2-hydrazinylpyridine

<formula> formula see original document page 67 </formula>

To a solution of 2-chloro-3-bromopyridine (14.5 g, 75.1 mmol) in 100 mL of dioxane was added anhydrous hydrazine (35.4 mL, 1127 mmol) at room temperature. The reaction mixture was heated to reflux for 15 hours, and then cooled to room temperature. Since most of the solvent was removed under reduced pressure, the residue was diluted with ethyl acetate, washed with water, dried over Na 4 SO 4, and concentrated. Recrystallization from ethyl acetate and hexanes afforded compound 11A (12.9 g, 91%) as a solid. LC / MS (m / z) = 188 (M + H) +.

Compound 11B. N'-S-Bromopyridin-1 O-10-methoxybicyclo [R] 4-heptane-1-carbobrazide.

<formula> formula see original document page 67 </formula>

To a stirred solution of 4-methoxybicyclo [2,2,1] heptane-1-carboxylic acid (4.7 g, 27.6 mmols; see Adcock, Abeywickrema and Kok, J., Org.Chem. 1984, 49, 1387 - 1397) in 90 mL of anhydrous THF was added NMM (3.6 mL, 32.7 mmol) and isobutyl chloroformate (4.3 mL, 32.7 mmol) at 0 ° C. The reaction was stirred at 0 ° C for 30 minutes, and then Compound 11A (5.2 g, 27.7 mmol) was added at 0 ° C. The resulting mixture was stirred at 0 ° C for 30 minutes followed by 5 hours at room temperature before quenching with water. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried over Na 2 SO 4 and concentrated. Purification by silica gel chromatography (10-50% ethyl acetate in hexanes) provided compounds 11B as a light yellow foam solid (7.0 g, 75%). HPLC tA (Method A): 1.25 min. LC / MS (m / z) = 340 (M + H) +.

Compound 11C. e-Bromo-3- (4-methoxybicyclo [2,2,1] heptan-1-yl- [1,2,4] triazo [4,3-a] pyridine.

<formula> formula see original document page 68 </formula>

To Compound 11B (700 mg, 2.1 mmol) in 14 mL of anhydrous α, α, α-triflurotoluene was added glacial acetatic acid (3 mL, 52.5 mmol) at room temperature. The reaction was performed in a micro-da reactor (Emrys Optimizer, Personal Chemistry, Biotage) at 200 ° C for 30 minutes. A total of 7 g of compound 11B were repeated in 10 series. The reaction mixtures were combined and concentrated under reduced pressure.

The residue was dissolved in ethyl acetate, washed with 1N NaOH, water, dried over Na 2 SO 4 and concentrated. Purification by silica gel chromatography (20 - 80% ethyl acetate in hexanes) provided compounds 11C as a white solid (5.7 g, 86%). HPLC tA (Method A): 2.07 minutes. LC / MS (m / z) = 323 (M + H) +.

D. 11- 4- (8-Bromo- [1,2,4] triazolo [4,3-a] pyridin-3-yl) bicyclo [2,2,1] hep-tan-1-ol

<formula> formula see original document page 68 </formula>

Compound 11C (500.0 mg, 1.55 mmol) was slowly dissolved in 48% aqueous HBr solution (8 mL, 70.7 mmol), followed by addition of acetic anhydride (3.4 mL, 36 mmol) ). The reaction was heated to 120 ° C for 14 hours, cooled to room temperature, and concentrated under reduced pressure. It was diluted with ethyl acetate, washed with 1 N NaOH, water, dried over NaaSO 4 and concentrated. Purification by silica gel decromatography (100% ethyl acetate to 5% methanol and ethyl acetate) provided 11D (445 mg, 93%) as a white solid. HPLC tA (Method A): 1.59 minutes. LC / MS (m / z) = 308 (M + H).

Example 11

To a solution of compound 11D (30 mg, 0.097 mmol) in DMFanhydrous (0.5 mL) was added 2-chloro-5-methylphenol (69 mg, 0.49 mmol) and anhydrous Cs2 CO3 powder (159 mg, 0, 49 mmol). The reaction was performed in a microwave reactor (Emrys Optimizer, Personal Chemistry, Biotage) at 180 ° C for 3.4 hours. Additional 2-chloro-5-methylphenol (69 mg, 0.49 mmol) and anhydrous Cs2 CO3 powder (159 mg, 0.49 mmol) were added, and sandbling was performed at 180 ° C for another 3 hours. The reaction mixture was diluted with ethyl acetate, washed with 1N NaOH, water, dried over MgSO4 and concentrated. Purification by preparative HPLC provided example 11 as white solid (31 mg, 66%) as TFA salt. HPLC tA (Method A): 2.90 minutes. LC / MS (m / z) = 370 (M + H) +. 1H NMR (CDCl3): δ7.84 (d, J = 7.2 Hz, 1H), 7.36 (d, J = 7.7 Hz, 1H), 7.06 (s, 1H), 7.05 (d, J = 8.8 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.30 (d, J = 7.2 Hz, 1H), 2.28 - 2 , 40 (m, 2H), 2.33 (s, 3H), 2.23 (s, 2H), 2.12 - 2.22 (m, 2H), 1.86 - 2.03 (m, 4H ).

EXAMPLES 12 TO 183

Examples 12 to 183 in Table 1 were synthesized according to the procedures described in Examples 1 to 11 in the schemes, or other similar methods known to one of ordinary skill in the art, with other appropriate reagents.

TABLE 1

<table> table see original document page 69 </column> </row> <table> <table> table see original document page 70 </column> </row> <table> <table> table see original document page 71 < / column> </row> <table> <table> table see original document page 72 </column> </row> <table> <table> table see original document page 73 </column> </row> <table> <table> table see original document page 74 </column> </row> <table> <table> table see original document page 75 </column> </row> <table> <table> table see original document page 76 < / column> </row> <table> <table> table see original document page 77 </column> </row> <table> <table> table see original document page 78 </column> </row> <table> <table> table see original document page 79 </column> </row> <table> <table> table see original document page 80 </column> </row> <table> <table> table see original document page 81 < / column> </row> <table> <table> table see original document page 82 </column> </row> <table> <table> table see original document page 83 </column> </row> <table> <table> table see original document page 84 </column> </row> <table> <table> table see original document page 85 </column> </row> <table> <table> table see original document page 86 </column> </row> < table>

Claims (13)

1. A compound characterized by the fact that it has the formula (I) <formula> formula see original document page 87 </formula> enantiomers, diastereomers, solvates, salts or prodrugs of the same compound as: W is aryl, cycloalkyl, heteroaryl or heterocyclyl, all of which may be optionally substituted with R 1, R 1, R 1, R 1, R 1 and R 2; R 1, R 1, R 1, R 1, R 1 and R 2 are independently hydrogen, halogen, -CONR2R2a, -SO2NR2R2a, -SOR2a, -SO2R2a, -NR2SO2R6, -NR2CO2Re, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, alkenyl, haloalkoxy, alkylthio, arylthio, arylsulfonylamino, heteroaryl or heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7b, and R 7c, or alternatively any of two R 1, R 1, R 1, Rib, Ric and Rid may be taken together to form a fused aryl, heteroaryl, heterocyclyl ring or heterocyclyl spiro ring; L is a ma, O, S, SO, SO2, alkenyl, cycloalkyl, NR5, CR2R2a, CR2R2aCR2bR2c, SO2NR2, OCR2R2a, OCR2R2aCR2aO, CR2bR2cCR2R2a2, CR2R2, CR2R2, CR2a SOCR2R2a, SO2CR2R2a, CR2R2aOCR2bR2c, CR2R2aSCR2bR2c, CR2R2aS02CR2bR2c, S02NR2CR2aR2b, COCR2R2a, CR2R2aCO, CON R5c R 2a R 2b, CR2R2aCR2bR2cS, CR2R2aCR2bR2cSO, CR2R2aCR2bR2cS02, with the proviso that L is not a quandoW connection is phenyl, R2, R2a> R2b and R2c are independently hydrogen, halogen, alkyl or haloalkyl, or alternatively any two R2, Ffea. R 2b, and R 2c may be taken together at the atom to which they are attached to form a halogen-substituted cycloalkyl, cycloalkyl or heterocyclyl ring; R 3, R 3a and R 3b are independently hydrogen, halogen, -OH, -CN, -NO 2, -CO 2 R 2a, - CONR2R2a, -SO2NR2R2a, -SOR2a, -SO2R2a, -NR2SO2R6, -NR2cO2R6, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, alkylnyl, haloalkoxy, alkylthio, arylthio, arylsulfonyl, amino heteroaryl or heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7b, and R 7c; R 4 is bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl, both of which may optionally be substituted with one or more selected halogen substituents, -OH, -OR6, -SR6, -OCOR6, -CN, -NR5COR6, -NR5SO2R6, -COR6, -CO2R6, -CO2H, -OCONR2R2a, -CONR 2 R 2a, -NR 5 CO 2 R 6, -SO 2 R 6, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, aryl 1α, heteroaryl or heterocyclyl may optionally be substituted with R 7, R 7a, R 7b, and R 7c; or R4 is cycloalkyl, other than bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl, which may be optionally substituted with one or more halogen substituents, -OH, -OR6, -SR6, -OCOR6, -CN, -NR5COR6, -NR5SO2R6, -COR61 -CO2R6, -CO2H1 -OCONR2R2ai -CONR2R2a, -NR5CO2R6, -SO2R61 alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkyl, aryl, alkoxy, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7bl and R 7c; or R 4 is heterocyclyl which may be optionally substituted with one or more substituents selected from halogen, -OH, -OR 6, -SR 6, -OCOR61-CN, -NR 5 COR 6, -NR 5 SO 2 R 6, -COR 6, -CO 2 H, -CO 2 R 2a, -CONR 2 R 2a, -NR 5 CO 2 R 6, -SO 2 R 61 alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted by R 7, R 7a, R 7b, and R 7c; is independently hydrogen, alkyl, cycloalkyl, aryl, haloalkyl, COR 2a, CO 2 R 2a, SO 2 NR 2 R 2a, or SO 2 R 2a; R 6, at each occurrence, is independently alkyl, cycloalkyl, aryl or heteroaryl, all of which may be optionally substituted with R 7, R 7a, R? b, and R 7c; and R7, R7ai R7b, and R7Q1 at each occurrence are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amine, -OH, heteroalkyl , heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, -NO 2, -CN or thiol. A compound according to claim 1, characterized in that: W is aryl, cycloalkyl or heteroaryl, all of which may be optionally substituted with Ri, Ria, Rib, Ric and Ria; Ri, Ria, Rib, Ric and Rid are independently hydrogen, halogen, -OH, -CN, -NO 2 t -CO 2 R 2a, -CONR 2 R 2a, -SO 2 NR 2 R 2a, -SOR 2a, -SO 2 R 2a, -NR 2 SO 2 R 6, alkyl, haloalkyl, cycloalkyl, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino: aminoalkyl, arylamino, heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7b, and R 7c; O, S, SO, SO2, NR2, CR2R2a, CR2R2aCR2bR2c, SO2NR2, OCR2R2a, CR2R2aO, SCR2R2a, CR2R2aS1 SOCR2R2a, SO2CR2R2a, CR2R2aOCR2bR2c, CR2R2aSCR2bR2c, CR2R2aSO2CR2bR2c, SO2NR2CR2aR2bou CONR5CR2aR2b, R2, R2a, R2b and R2c are independently hydrogen, halogen, alkyl or haloalkyl: R3, R3a and R3b are independently h idogen, halogen, -OH, -CN, -NO2, -CO2R2a, -CONR2R2a, -SO2NR2R2a, -SOR2a, -SO2R2a, -NR2SO2R6, -NR2CO2R6, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkyl, haloalkyl alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamino, heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c; 2] octyl or bicyclo [2.2.1 jheptyl, both of which may optionally be substituted with one or more selected halogen substituents, -OH1 -OR6, -SR6, -OCOR6, -CN, -NR5COR6, -NR5SO2R6, -COR 6 -1 -CO 2 R 6, -CO 2 H 1 -OCONR 2 R 2a, -CONR 2 R 2a, -NR 5 CO 2 R 6 1 -SO 2 R 6, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c; or R4 is cycloalkyl, other than bicyclo [2,2,2] octyl or bicyclo [2,2,1 Jheptila, which may be optionally substituted by one or more halogen substituents, -OH 1 -OR 6, -SR 6, - OCOR6, -CN, -NR5COR6l -NR5SO2R6, -COR6l -CO2R6l -CO2H1 -OCONR2R2ai -CONR2R2ai -NR5CO2R6, -SO2R6l alkyl, where alkoxy, aryl, amine, heterocyclyl or heteroaryl can be alkyl, heteroaryl, optionally substituted with R7l R7ai R7b, and R7c; or R 4 is heterocyclyl, which may be optionally substituted by one or more substituents selected from halogen, -OH, -OR 6 1 -SR 6, -OCOR 6 -C-N, -NR 5 COR 6, -NR 5 SO 2 R 6, -COR 6 1 -CO 2 R 6, -CO 2 H 1 -OCONR 2 R 21a-CONR 2 R 2a, - NR 5 CO 2 R 6, -SO 2 R 6 alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a R 7b, and R 7c; R 5 at each occurrence is independently hydrogen, alkyl , cycloalkyl, aryl, haloalkyl, COR2a or COsFi2a ', R6, at each occurrence, is independently alkyl, cycloalkyl, aryl or heteroaryl, all of which may be optionally substituted with R7l R7a, R7bl and R7c; and R 7, R 7a, R 7b, and R 7c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arHaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyl, amine, -OH 1-hydroxy, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, -NO2l -CN or thiol. A compound according to claim 1, characterized in that: W is aryl, cycloalkyl or heteroaryl, all of which may be optionally substituted with R1, R1a, Rib, Ric and R1ci; R1l R1a, Rib, Ric and R1d are independently hydrogen, halogen, -OH, -CN, -NO2, -CO2R2a, -CONR2R2a, -SO2NR2R2a, -SOR2a, -SO2R2a, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, aryl alkylamino, aminoalkyl, arylamino, heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c; L is a bond, O, S, SO R 2a, R 2a, R 2a, R 2a, R 2a, R 2a, R 2a, R 2a, R 2a, R 2a, R 2a, R 2a, R 2a, R 2a, R 2a, R 2a, R 2a, R 2a, R 2a, R 2a, R 2a, R 2a, R 2a, R 2a, R 3a, R 2a, R 3a, R 2a, R 3a, R 2a, R 3a, R 2a, R 2a, R 3a, R 2a, R 2a, R 3a, R 2a, R 2a, R 2a, R 2a, R 2a, R 2a, R 6a, R 6a, R 6a, R 6a, R 6a, R 2a, R 6a, R 6a, R 6a, R 6a, R 7a, and R 6a, R 6a are R 2a 2 hydrogen, halogen, -OH, -CN, -NO2, -CO2R2a, -CONR2R2a, -SO2NR2R2a -SOR 2a, -SO 2 R 2a, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamino, heteroarylamino, aryl, heteroaryl or heterocyclyl, where aryl may be optional R 7 is R 7a, R 7a, R 7b, and R 7c; R 4 is bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl, both of which may optionally be substituted with one or more substituents selected from. halogen, -OH, -OR6, -SR6, -OCOR6, -CN, -COR6, -CO2R6, -CO2H, OCONR2R2a, -CONR2R2a, -SO2R6, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7b, and R 7c; or R4 is cycloalkyl, other than bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl, which may be optionally substituted with one or more halogen substituents, -OH, -OR6, -SR6 , -OCOR6, -CN, -COR6, -CO2R6, -CO2H, -OCONR2R2a, -CONR2R2a, -SO2R6, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7t, and R 7c; or R4 is heterocyclyl, which may optionally be substituted with one or more substituents selected from halogen, -OH, -OR6, -SRe, -OCOR6, -CN, -COR6, -CO2R6, -CO2H, -OCONR2R2a, -CONR2R2a, -SO2R6 alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7b, and R 7c; R 6 at each occurrence is independently alkyl, cycloalkyl, aryl or heteroaryl, all of which may be optionally substituted with R 7, R 7a, R 7b, and R 7c; and R 7, R 7a, R 7b, and R 7c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyl, amine, -OH 1-hydroxy, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, -NO 2, -CN or thiol. A compound according to claim 1, characterized in that: W is aryl or heteroaryl, both of which may be optionally substituted with R1, R1a, R1b, R1c and R1d; Ri, Ria, Rib, Ric and R1C ) are independently hydrogen, halogen, -OH, -CN, -NO 2, -CO 2 R 2a, -CONR 2 R 2a, -SO 2 NR 2 R 2a, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylsulfonyl, arylsulfonyl, aminoalkyl, arylamino, heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may optionally be substituted with R7, R7a, R7b, and R7c; L is a bond, O, S, SO, SO2, CR2R2a , OCR2R2a, CR2R2aO, SO2NR2CR2aR2b or CR2R2aOCR2bR2c; R2, R2a, R2b and R2c are independently hydrogen, halogen, alkyl or haloalkyl; R3, R3a and R3b are independently hydrogen, halogen, -OH, -CNCO, -NO2, -NO2, CONR 2 R 2a, -SO 2 NR 2 R 2a, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl 1A, alkylamino, aminoalkyl, arylamino, heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein aryl, heteroaryl or heterocyclyl may be optionally substituted by R 7, R 7a, R 7b, and R 7c; R 4 is bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl, both of which may optionally be substituted with one or more selected halogen substituents, -OH, -OR 6, -SR 6, -OCOR 6, -CN 1 -COR 6, -CO 2 R 6, - CO 2 H, -OCONR 2 R 2a, -CONR 2 R 2a, -SO 2 R 6, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7b, and R7c; or R4 is cycloalkyl, other than bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl, which may be optionally substituted with one or more halogen substituents, -OH, -OR6, -SR6, -OCOR6, -CN, -COR6, -CO2R6, -CO2H, -OCONR2R2a, -CONR2R2a, -SO2R6, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may optionally be substituted with R 7, R 7a, R 7b, and R 7c; or R 4 is heterocyclyl, which may be optionally substituted by one or more substituents selected from halogen, -OH, -OR 6, -SR 6, -OCOR 6, -CN, -COR 6, -CO 2 R 6, -CO 2 H, -OCONR 2 R 2a, -CONR 2 R 2a, -SO 2 R 6 alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7b, and R 7c; R 6 at each occurrence is independently alkyl, cycloalkyl, aryl or heteroaryl, all of which may be optionally substituted with R 7, R 7a, R 7b, and R 7c; and R 7, R 7a, R 7b, and R 7c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amine, -OH, hydroxy , heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, -NO 2, -CN or thiol. A compound according to claim 1, characterized in that: W is aryl or heteroaryl, both of which may be optionally substituted with R1, R1a, Rit>, Ric and Rm; R1, R1a, R1b, B1c and R 1d are independently hydrogen, halogen, -OH, -CN, -NO 2, -CO 2 R 2a, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamino, heteroaryl aryl, heteroaryl or heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, Rya, R7b, and R7c; L is a bond, O, S, SO, SO2, CR2R2a, OCR2R2a, CR2R2aO, SO2NR2CR2aR2b or CR2R2aOCR2bR2C; R2, R2a, R2b and R2c are independently hydrogen, halogen, alkyl or haloalkyl; R3, R3a and R3b are independently hydrogen, halogen, -OH, -CN, -NO2, -CO2R2a, alkyl, haloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamino, heter arylamino, aryl, heteroaryl or heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7b, and R 7c; R 4 is bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl , both of which may optionally be substituted by one or more halogen-selected substituents, -OH, -OR6, -SR6, -CN, -COR6, -CO2R6, -CO2H, -CONR2R2a, -SO2R6, alkyl, alkoxy, aryl amine, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7b, and R 7c; or R 4 is cycloalkyl, other than bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl, which may be optionally substituted by one or more halogen substituents, -OH, -OR 6, -SR 6l -CN, -COR61 -CO 2 R 6, -CO 2 H, -CONR 2 R 2a, -SO 2 R 6, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a R7b and R7c; or R 4 is heterocyclyl, which may be optionally substituted by one or more substituents selected from halogen, -OH, -OR 6, -SR 6, -CN, -COR 6, -CO 2 R 6, -CO 2 H, -CONR 2 R 2a, -SO 2 R 6, alkyl, alkoxy, aryl amino, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7b, and R 7c; R 6, at each occurrence, is independently alkyl, cycloalkyl, aryl or heteroaryl, all of which may be optionally substituted with R7, R7a, R7b, and R7c; and R 7, R 7a, R 7b, and R 7c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amine, -OH, hydroxy , heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, -NO 2, -CN or thiol. A compound according to claim 1, characterized in that: W is aryl which is optionally substituted with Ri, Ria, Rib, Rice R1d; Ri, Ria, Rib, Ric and Rm are independently hydrogen, halogen, -OH, -CN, -NO 2, alkyl haloalkyl, cycloalkyl, alkoxy, aryloxy, haloaloxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamino, heteroaryl, aryl, heteroaryl or heterocyclyl, wherein aryl, or heterocyclyl may be optionally substituted with R 7, R 7a, R 7b, and R 7c; L is a bond, O, S, SO, SO 2, CR 2 R 2a, OCR 2 R 2a, CR 2 R 2a O, SO 2 NR 2 r 2a R 2b or CR 2 R 2aOCR 2b R 2c; R3, R3a and R3b are independently hydrogen, halogen, -OH, -CN, -NO2, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, heteroaryl, aryl -amino, aryl, heteroaryl or heterocyclyl, wherein aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7b, and R 7c; R 4 is bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl, both of which may be optionally substituted. with one or more halogen-selected substituents, -OH, -OR6, -SR6, -CN, -COR6, -CO2R6, -CO2H, -CONR2R2a, -SO2R6, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted by R 7, R 7a, R 7b, and R 7c; or R4 is cycloalkyl, other than bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl, which may be optionally substituted by one or more halogen substituents, -OH 1 -OR 6, -SR 6, -CN, -COR 6, -CO 2 R 6, -CO 2 H, -CONR 2 R 2a, -SO 2 R 6, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7b, and R 7c; R 6 at each occurrence is independently alkyl, cycloalkyl, aryl or heteroaryl, all of which may be optionally substituted with R 7, R 7a, R 7b, and R 7c; and R 7, R 7a, R 7b, and R 7c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amine, -OH, hydroxy , heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, -NO 2, -CN or thiol. A compound according to claim 1, characterized in that: W is aryl which is optionally substituted with Ri, Ria, Rib, R1c and R1d; Ri, Ria, Rib, Ric and Rid are hydrogen, halogen, - OH, -CN, -NO 2, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, aryl, heteroaryl or heterocyclyl, where aryl, heteroaryl or heterocyclyl may be optionally substituted R7a, R7a, R7b, and R7c; L is a bond, O, S, CR2R2a, OCR2R2a, CR2R2aO orCR2R2aOCR2bR2c; Ra, R2a, R2b and R2c are independently hydrogen, halogen, alkyl or haloalkyl; R3, R3a and R3 are independently hydrogen, halogen, -OH, -CN, -NO2, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, aryl, heteroaryl or heterocyclyl, wherein aryl, heteroaryl or heteroaryl may optionally be substituted with R7, R7a, R7b, and R7 R4 is bicyclo [2,2,2] octyl or bicyclo [2,2,1 jheptyl, both of which may be optionally substituted with one or more selected halogen substituents, -OH 1 -OR 6, -SR 6, -CN -COR6, -CO2 R6, -CO2 H, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c; or R 4 is cycloalkyl, other than bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl, which may be optionally substituted by one or more halogen substituents, -OH, -OR 6, -SR 6l -CN, -COR6, -CO2 R6, -CO2 H, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7a, R7b, and R7c R 6, at each occurrence, is independently alkyl, cycloalkyl, aryl or heteroaryl; and R 7, R 7a, R 7b, and R 7c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amine, -OH, hydroxy , heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, -NO 2, -CN or thiol. A compound according to claim 1, characterized in that: W is phenyl which is optionally substituted by R 1, R 1, R 1, R 1c β R 1d, R 1, R 1a, R 1b, R 1c and R 1d are independently hydrogen, halo, genius, -OH, -CN, -NO2, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloaloxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, aryl, heteroaryl or heterocyclyl; L is O, S, SCH2, OCH2, R 3, R 3a and R 3b are independently hydrogen, halogen, -OH 1 -CN, -NO 2, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylheteroaryl; R 4 is bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl, all of which may be optionally substituted with one or more selected halogen substituents, -OH, -OR 6, -SR 6, -CN alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7b, and R 7c; R 6 at each occurrence is independently alkyl, cycloalkyl, aryl or heteroaryl; and R 7, R 7a, R 7bi and R 7C at each occurrence are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylalkyl, cycloalkyl, amine, -OH, hydroxyalkyl, heteroaryl, heteroaryloxy, heteroarylalkyl, alkylthio, arylNO 2, or - CN. A compound according to claim 1, characterized in that it has the formula IA: wherein: L is selected from O, S, OCH2, CH2OCH2 and SO2NHCH2; and R3, R3a and R3b are independently selected from hydrogen, halogen, -CF3, OCF3, alkyl or alkoxy; wherein: R1, Ria, Rib, Ric and Rid are independently hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl or heterocyclyl; L is O; R3. Rea and R3b are independently selected from hydrogen or halogen, R4 is bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl, both of which may optionally be substituted with one or more substituents selected from R 2b. halogen, -OH, -OR 6, -OCOR 6, haloalkyl, haloalkoxy, aryl or heterocyclyl; e R 6, at each occurrence, is independently alkyl, or cycloalkyl; wherein: L is selected from O, OCH 2 and CH 2 OCH 2, R 4 is bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl, both of which may optionally be substituted with one or more substituents selected from halogen, -OH, -OR6, -SR6, -OCOR6, -CN, -NR5COR6, -NR5SO2R6, -COR6, -CO2R6, -CO2H, -OCONR2R2a, -CONR2R2a, -NR5CO2R6, -SO2R6, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7b, and R 7c; or R4 is cycloalkyl, other than bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl, which may be optionally substituted with one or more halogen substituents, -OH, -OR6, -SR6 -OCOR6, -CN, -NR5COR6, -NR5SO2R6, -COR6, -CO2R6, -CO2H, -OCONR2R2a, -CONR2R2a, -NR5CO2R6, -SO2R6, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, where a Alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7b. and Rzc. ' e R 6, at each occurrence, is independently alkyl or cycloalkyl; where: L is selected from O, OCH 2 and CH 2 OCH 2; R 4 is a fused or bridged cycloalkyl, other than bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl, which may optionally be substituted with one or more substituents selected from halogen, -OH, -ORe, -SR6, -OCOR6, -CN, -NR5COR6, -NR5SO2R6, -COR6, -CO2R6, -CO2H, -OCONR2R2a, -CONR2R2a, -NR5CO2R6l -SO 2 R 6, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7t>, and R 7c; e R 6, at each occurrence, is independently alkyl or cycloalkyl. Pharmaceutical composition, characterized in that it comprises a compound as defined in claim 1. Use of a compound of formula I as defined in any one of claims 1 to 9, characterized in that it is for the preparation of a pharmaceutical composition for treating, preventing, or reducing the progression of a disease requiring inhibitor therapy. 11-beta-hydroxysteroid dehydrogenase type I. Use of a compound of formula I as defined in any one of claims 1 to 9, characterized in that it is for the preparation of a pharmaceutical composition for treating, preventing, or reducing the progression of diabetes, hyperglycemia, obesity, dyslipidemia, hypertension, cognitive impairment, rheumatoid arthritis, osteoarthritis, glaucoma, and metabolic syndrome. Use of a compound of formula I as defined in any one of claims 1 to 9, characterized in that it is for the preparation of a pharmaceutical composition for inhibiting the type IW 11-beta-hydroxysteroid dehydrogenase enzyme is aryl; R 2a, R 2b and R 2c are independently hydrogen, halogen, alkyl or haloalkyl, or alternatively any two R 2, R 2a, R 2, and R 2c may be taken together at the atom to which they are attached to form a halogen-substituted cycloalkyl or heterocyclyl cycloalkyl ring R3, Rea and R3b are independently hydrogen, halogen, -OH, -CN1 -NO2, -CO2R2a, -CONR2R2a, -SO2NR2R2a, -SOR2a, -SO2R2a, -NR2SO2R6, -NR2CO2R6l alkyl, haloalkyl, cycloalkyl, cycloalkyl, alkenyl, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamine, aminoalkyl, arylamine, heteroarylamine, aryl, heteroaryl or heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may be optionally substituted R 7 is R 7a, R 7a, R 7b, and R 7C; R 4 is bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl, both of which may optionally be substituted with one or more halogen-selected substituents, -OH, -OR6, -SR6, -OCOR6, -CN, -NR5COR6, -NR5SO2R6, -COR6, -CO2R6, -CO2H, -OCONR2R2a, -CONR2R2a, -NR5CO2R6, -SO2R6, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7b, and R 7c; or R4 is cycloalkyl, other than bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl, which may be optionally substituted with one or more halogen substituents, -OH, -OR6, -SR6 , -OCOR6, -CN, -NR5COR61 -NR5SO2R6, -COR6, -CO2R6, -CO2H, -OCONR2R2a, -CONR2R2a, -NR5CO2R6, -SO2R6, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7ai R 7b, and R 7c; or R 4 is heterocyclyl, which may be optionally substituted by one or more substituents selected from halogen, -OH, -OR 6, -SR 6, -OCOR61 -CN 1 -NR 5COR61 -NR 5 SO 2 R 6 1 -COR61 -CO 2 R 6, -CO 2 H, -OCR 2 R 2a, -CONR 2 R 2a, - NR 5 CO 2 R 6, -SO 2 R 6, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7b. and R 7c; R 5 at each occurrence is independently hydrogen, alkyl, cycloalkyl, aryl, haloalkyl, COR 2a, CO 2 R 2a, SO 2 NR 2 R 2a, or SO 2 R 2a; R 6 at each occurrence is independently alkyl, cycloalkyl, aryl or heteroaryl all of which may be optionally substituted with R7, R7a, R7b, and R7c; and R 7, R 7a, R 7b, and R 7c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amine, -OH, hydroxy , heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamine, arylcarbonylamine, -NO 2, -CN or thiol.12. A method for treating, preventing, or reducing the progression of diabetes, hyperglycemia, obesity, dyslipidemia, hypertension, cognitive impairment, rheumatoid arthritis, osteoarthritis, glaucoma and Metabolic Syndrome, which comprises administering to a mammal patient in need of treatment. a therapeutically effective amount of a compound of formula I <formula> formula see original document page 102 </formula> enantiomers, diastereomers, solvates, salts or prodrugs of the same as: W is aryl, cycloalkyl, heteroaryl or heterocyclyl, all of which may be optionally substituted with R 1 R 1a, R 1b, Ric and Rm; R 11 R 1a, Rib, Ric and Rid are independently hydrogen, halogen, -OH 1 -CN, -NO 2, -CO 2 R 2a, -CONR 2 R 2a, -SO 2 NR 2 R 2a, -SOR 2a , -SO 2 R 2a, -NR 2 SO 2 R 6, -NR 2 cO 2 R 6, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, alkenyl, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamine, aminoalkyl, arylamine, heteroaryloyl, aryl or heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7b, β R 7 or alternatively any of R 1, R 1a, R 1bl Ric and R 1cj may be taken together to form a fused aryl, heteroaryl, heterocyclyl ring or ring L is a bond, O, S, SO, SO2, alkenyl, cycloalkyl, NR5, CR2R2a, CR2R2aCR2bR2c, SO2NR2, OCR2R2a, OCR2R2aCR2bR2a, CR2bR2c2, R2a2 CR2R2a2 CR2R2aS, CR2R2aSO, CR2R2aSO2, SOCR2R2a, SO2CR2R2a, CR2R2aOCR2bR2c, CR2R2aSCR2bR2c, CR2R2aSO2CR2bR2c, SO2NR2CR2aR2b, COCR2R2a, CR2R2aCO, CONR5CR2aR2b, CR2R2aCR2bR2cS, CR2R2aCR2bR2cSO, CR2R2aCR2bR2cSO2, with the proviso that L is not a quandoW connection is aryl; R2, R2a, R2b and R 2c are independently hydrogen, halogen, alkyl or haloalkyl, or alternatively any two R 2, R 2a, R 2b, and R 2c may be taken together with the atom to which they are attached to form a decycloalkyl ring, cycloalkyl. halogen substituted alkyl or heterocyclyl: R 3, Rea and R 3b are independently hydrogen, halogen, -OH, -CN, -NO 2, -CO 2 R 2a, -CONR 2 R 2a, -SO 2 NR 2 R 2a, -SOR 2a, -SO 2 R 2a, -NR 2 SO 2 R 6, -NR 2 cO 2 R 6, alkyl, , cycloalkyl, alkoxy, aryloxy, alkenyl, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamine, aminoalkyl, arylamine, heteroarylamine, aryl, heteroaryl or heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7b, and R 7c: R 4 is bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl, both of which may optionally be substituted with one or more halogen-selected substituents, -OH , -OR6, -SR6, -OCOR6, -CN1-NR5COR6, -NR5SO2R6, -COR6, -CO2R6, -CO2H, -OCONR2R2a, -CONR2R2a, -NR5CO2R6, -SO2R6, alkyl, alkoxy, aryl, heteroaryl or heterocyclyl wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7b, and R 7c; or R4 is cycloalkyl, other than bicyclo [2,2,2] octyl or bicyclo [2,2 (1] heptyl), which may optionally be substituted with one or more halogen substituents, -OH, -OR6, -SR6 , -OCOR6, -CN1 -NR5COR6, -NR5SO2R6, -COR6, -CO2R6, -CO2H, -OCONR2R2a, -CONR2R2a, -NR5CO2R6, -alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7b, and R 7c; or R 4 is heterocyclyl which may be optionally substituted by one or more substituents selected from halogen, -OH, -OR 6, -SR 6, -OCOR6, -CN1 -NR5COR6, -NR5SO2R61 -COR6, -CO2R61 -CO2H, -OCONR2R2ai-CONR2R2a, -NR5CO2R6, -SO2R6, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7t, and R 7c; R 5 at each occurrence is independently hydrogen, alkyl, cycloalkyl, aryl, haloalkyl a, COR 2a, CO 2 R 2a, SO 2 NR 2 R 2a, or SO 2 R 2a; R 6, at each occurrence, is independently alkyl, cycloalkyl, aryl or heteroaryl, all of which may be optionally substituted with R 7, R 7a, R 7b, and R 7c; and R 7, R 7a, R 7b, and R 7c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amine, -OH, hydroxy , heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamine, arylcarbonylamine, -NO 2, -CN or thiol.13. A method of inhibiting the type I 11-beta-hydroxysteroid dehydrogenase enzyme comprising administering to a mammalian patient in need of treatment a therapeutically effective amount of a compound of formula I <formula> formula see original document page 104 </formula> enantiomers, diastereomers , solvates, salts or prodrugs of the same wherein: W is aryl, cycloalkyl, heteroaryl or heterocyclyl, all of which may be optionally substituted with R1, Ria, Rib, Ric and Rid; R1. Ria, Rib, Ric and R-id are independently hydrogen, halogen, -OH, -CN, -NO2, -CO2R2a, -CONR2R2a, -SO2NR2R2a, -SOR2a, -SO2R2a, -NR2SO2R6, -NR2CO2R6, alkyl, haloalkyl , cycloalkyl, alkoxy, aryloxy, alkenyl, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamine, aminoalkyl, arylamine, heteroarylamine, aryl, heteroaryl or heterocyclyl, wherein aryl, heteroaryl or heterocyclyl may be optionally substituted with R7, R7b, β R7c, or alternatively any two R1, Ria, Rib, Ric and Rid may be taken together to form a fused aryl, heteroaryl, heterocyclyl ring or spiro heterocyclyl ring; L is a bond, O, S, SO, SO2, alkenyl, cycloalkyl, NR5, CR2R2a, CR2R2aCR2bR2c, SO2NR2, OCR2R2a, OCR2R2aCR2bR2c, CR2R2aO, CR2bR2cCR2R2aO, N (R) CR2R2a, CR2R2aN (Rs), SCR2R2a, CR2R2aS, CR2R2aSO, CR2R2aSO2, SOCR2R2a, SO2CR2R2a, CR2R2aOCR2bR2c, CR2R2aSCR2bR2c, CR2R2aSO2CR2bR2c, SO2 N R2cR2a R2b, COCR2R2a, CR2R2aCO, CONR5CR2aR2b, CR2R2aCR2bR2cS, CR2R2 aCR2bR2cSO, CR2R2aCR2bR2cSO2, provided that L is not a bond when W is aryl R2, R2a, R2b and R2c are independently hydrogen, halogen, alkyl or haloalkyl, or alternatively any of R2, R2a, R2b, and R2c may be taken together. to the atom to which they are attached to form a halogen substituted heterocyclyl, cycloalkyl, cycloalkyl ring; R3, R3a and R3b are independently hydrogen, halogen, -OH, -CN, -NO2, -CO2R2a, -CONR2R2a, -SO2NR2R2a, -SOR2a , -SO 2 R 2a, -NR 2 SO 2 R 6, -NR 2 cO 2 R 6, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, alkenyl, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamine, aminoalkyl, arylamine, heteroarylaryl, aryl heteroaryl, aryl , heteroaryl or heterocyclyl may optionally be substituted with R 7, Fba, Fta. and Ryc; R4 is bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl, both of which may optionally be substituted with one or more selected halogen substituents, -OH, -OR61 -SR6, -OCOR6, -CN, -NR5COR6, -NR5SO2R6, -COR6, -CO2R6, -CO2H, -OCONR2R2a, -CONR2R2a, -NR5CO2R6, -SO2R6, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein Quyl, alkoxy, aryl, heteroaryl or heterocyclyl may optionally be substituted with R 7, R 7a, R 7b, and R 7c; or R 4 is cycloalkyl, other than bicyclo [2,2,2] octyl or bicyclo [2,2,1] heptyl, which may optionally be substituted with one or more substituents selected from halogen, -OH, -OR 6, -SR 6 , -OCOR6, -CN, -NR5COR6, -NR5SO2R6, -COR6, -CO2R6, -CO2H, -OCONR2R2a, -CONR2R2a, -NR5CO2R61 -SO2R6, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, where aalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7ai R 7b, and R 7c; or R 4 is heterocyclyl, which may be optionally substituted by one or more substituents selected from halogen, -OH, -OR 6, -SR 61 -OCOR 6, -CN, -NR 5 COR 6, -NR 5 SO 2 R 6, -COR 6, -CO 2 R 6, -CO 2 H 2, -OCONR 2 R 2a, -CONR 2 R 2a, -NR 5 CO 2 R 6, -SO 2 R 6, alkyl, alkoxy, aryl, amine, heterocyclyl or heteroaryl, wherein alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substituted with R 7, R 7a, R 7bl and R 7c; is independently hydrogen, alkyl, cycloalkyl, aryl, haloalkyl, COR2a, CO2R2ai SO2NR2R2ai or SO2R2a; R6 at each occurrence is independently alkyl, cycloalkyl, aryl or heteroaryl, all of which may be optionally substituted with R7, R7a, R7b, and R7c ; and R 7, R 7a, R 7b, and R 7c, at each occurrence, are independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amine, -OH, hydroxy , acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamine, arylcarbonylamine, -NO 2, -CN or thiol.